Alpha adrenergic receptor agonists for treatment of degenerative disc disease

ABSTRACT

Effective treatments of pain and/or inflammation from degenerative disc disease and/or facet joint are provided. Through the administration of an effective amount of at least one alpha adrenergic agonist at or near a degenerative disc and/or facet joint, one can reduce, prevent or treat pain and/or inflammation caused by the degenerative disc disease and/or facet joint.

This application claims the benefit of the filing date of ProvisionalApplication No. 61/046,201, filed Apr. 18, 2008, entitled “ClonidineFormulations In A Biodegradable Polymer Carrier.” This entire disclosureis hereby incorporated by reference into the present disclosure.

BACKGROUND

The human spine is formed from twenty-six consecutive vertebrae. Each ofthese vertebrae is separated from any adjacent vertebra by anintervertebral disc that functions to absorb shock and prevent eachvertebra from directly impacting upon another vertebra. At the center ofeach disc is a nucleus pulposus that contains proteoglycan. Around thenucleus pulposus is an outer ring called the annulus fibrosus.Degenerative disc disease refers to any of the common degenerativeconditions of the lower spine involving degeneration of the disc. Discdegeneration is often associated with the symptom of pain and may leadto inflammation and neuropathic pain, for example, spinal stenosis,spondylolisthesis, and retrolisthesis.

Disc degeneration associated with the aging process is generallyassociated with the loss of proteoglycan from the nucleus pulposus ofthe spinal discs and a reduction of the disc's ability to absorb shockbetween vertebrae. Although some affected patients may not exhibitsymptoms, many affected patients suffer from chronic back and/or legpain. Pain associated with disc degeneration may become debilitating andmay greatly reduce a patient's quality of life.

While non-operative treatments for disc degeneration exist, manypatients, for example, those patients with severe symptoms, may notrespond to non-operative treatment. Conventional operative treatmentgenerally involves spondylosyndesis (spinal fusion), which is highlyinvasive and is associated with certain risks to the patient.

While the biological mechanisms of degenerative disc disease are notwell known, it is known that proteoglycans, which are abundant in thedisc's nucleus pulposus, decline in content with age, are believed to bean important factor in the pathogenesis of the disease. Degenerated andherniated discs are known to produce increased amounts of proteins suchas nitric oxide (NO), cytokines, such as interleukin-1 (IL-1 andIL-1.beta.), interleukin-6 (IL-6) and TNF-alpha, prostaglandin E2 andmatrix metalloproteases (MMP). These proteins play a regulatory role inthe interactions between the biochemical agents produced by degenerateddiscs.

One drug class that is known to the medical profession is the alphaadrenergic receptor agonists. In general, the alpha-adrenergic receptorsmediate excitatory and inhibitory functions: alpha-1 adrenergicreceptors are typically excitatory post-synaptic receptors whichgenerally mediate responses in the effector organ, while alpha-2adrenergic receptors are located postsynaptically as well aspresynaptically, where they inhibit release of neurotransmitters.

Examples of alpha adrenergic receptor agonists used clinically to treatdifferent condition include clonidine, phenoxybenzamine and prazosin(for treatment of hypertension and opioid withdrawal), naphazoline (fornasal decongestion), UK-14,304 and p-aminoclonidine (for -glaucoma).

However, to date alpha adrenergic receptor agonists have not been widelyappreciated as effective treatments for pain and/or inflammationresulting from degenerative disc disease and/or facet joint pain andinflammation. Thus, there is a need to develop alpha adrenergic receptoragonists to prevent, treat or reduce pain and/or inflammation resultingfrom degenerative disc disease and/or facet joint pain and inflammation.

SUMMARY

Novel compositions and methods are provided for effectively reducing,preventing, or treating unwanted pain and/or inflammation resulting fromdegenerative disc disease and/or facet joint pain and inflammation. Thepain and/or inflammation may be reduced for extended periods of time. Invarious embodiments, alpha adrenergic agonist compositions and methodsare provided that may reduce the size of the disc herniation in a singledrug depot or multiple drug depots.

In one embodiment, an implantable drug depot is provided which is usefulfor reducing, preventing or treating pain and/or inflammation from adegenerative disc and/or facet joint in a patient in need of suchtreatment, the implantable drug depot comprising a therapeuticallyeffective amount of an alpha adrenergic agonist, the drug depot beingimplantable at or near the degenerative disc and/or facet joint toreduce, prevent or treat pain and/or inflammation from the degenerativedisc and/or facet joint, wherein the drug depot is capable of releasingan effective amount of the alpha adrenergic agonist over a period of atleast one day.

In another embodiment, a method is provided for treating pain and/orinflammation from a degenerative disc in a patient in need of suchtreatment, the method comprising administering one or more biodegradabledrug depots comprising a therapeutically effective amount of an alphaadrenergic agonist at or near the degenerative disc and/or facet joint,wherein the drug depot releases an effective amount of the alphaadrenergic agonist over a period of at least 1 day.

In yet another embodiment, a method is provided for reducing pain and/orinflammation from a degenerative disc in a patient in need of suchtreatment, the method comprising delivering one or more biodegradabledrug depots comprising a therapeutically effective amount of an alpha-2adrenergic agonist at or near the degenerative disc and/or facet jointof the patient, wherein the drug depot releases an effective amount ofthe alpha-2 adrenergic agonist over a period of at least 1 day.

In still yet another embodiment, an implantable drug depot is providedwhich is useful for reducing, preventing or treating pain and/orinflammation from a degenerative disc and/or facet joint in a patient,the implantable drug depot comprising a therapeutically effective amountof alpha-2 adrenergic agonist and a polymer; wherein the drug depot isimplantable at or near the degenerative disc and/or facet joint toreduce, prevent or treat pain and/or inflammation, and the depot iscapable of releasing (i) about 5% to about 20% of the alpha-2 adrenergicagonist relative to a total amount of the alpha-2 adrenergic agonistloaded in the drug depot over a first period of up to 72 hours and (ii)about 21% to about 99% of the alpha-2 adrenergic agonist relative to atotal amount of the alpha-2 adrenergic agonist loaded in the drug depotover a subsequent period of up to 6 months.

The compositions and methods provided may be used to reduce, prevent, ortreat inflammation and/or pain, including but not limited toinflammation and/or pain that follows surgery, chronic inflammatorydiseases, chronic inflammatory bowel disease, bursitis, osteoarthritis,osteolysis, tendonitis, sciatica, degenerative disc disease, fact jointpain and/or inflammation, stenosis, myopathy, spondilothesis, lower backpain, facet pain, carpal tunnel syndrome, tarsal tunnel syndrome, failedback pain or the like.

The pharmaceutical composition may for example, be part of a drug depot.The drug depot may: (i) consist of the alpha adrenergic receptor agonistand the biodegradable polymer(s); or (ii) consist essentially of thealpha adrenergic receptor agonist; or (iii) comprise the alphaadrenergic receptor agonist and one or more other active ingredients,surfactants, excipients or other ingredients or combinations thereof.When there are other active ingredients, surfactants, excipients orother ingredients or combinations thereof in the formulation, in someembodiments these other compounds or combinations thereof comprise lessthan 20 wt. %, less than 19 wt. %, less than 18 wt. %, less than 17 wt.%, less than 16 wt. %, less than 15 wt. %, less than 14 wt. %, less than13 wt. %, less than 12 wt. %, less than 11 wt. %, less than 10 wt. %,less than 9 wt. %, less than 8 wt. %, less than 7 wt. %, less than 6 wt.%, less than 5 wt. %, less than 4 wt. %, less than 3 wt. %, less than 2wt. %, less than 1 wt. % or less than 0.5 wt. %.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1A is a cross-sectional view of a target tissue site, which is adegenerative disc disease where the disc is herniated, but has notruptured.

FIG. 1B is a cross-sectional view of a target tissue site, which is adegenerative disc disease, which has herniated where the disc hasruptured.

FIG. 2 is a cross-sectional view illustrating one embodiment of theimplantable drug depot having an anchor attached to the drug depot by aline (e.g., suture, yarn, etc.) that is being administered into anintervertebral disc having an annulus.

FIG. 3 is a graphic representation of the thermal paw withdrawal latencyas a percentage from baseline for the following administrations using analpha-2 adrenergic receptor agonist: clonidine (CL) 0.02 mg/kg/daysubcutaneously, 100 DL 7E Control, 5% CL-HCL, CL 5%, CL 8%, 1 CL 7%, POEControl and POE CL-Base, at 7 days, 14 days, 21 days, 28 days, 35 days,42 days, 49 days, 56 days and 63 days. CL-HCL refers to clonidinehydrochloride. “POE” refers to poly(orthoester). “CL-Base” refers toclonidine in its base form.

FIG. 4 is a graphic representation of the mechanical threshold as apercentage from baseline for the following administrations: clonidine0.02 mg/kg/day subcutaneously, 100 DL 7E Control, 5% CL-HCL, CL 5%, CL8%, CL 7%, POE Control and POE CL-Base, at 8 days, 15 days, 22 days, 29days, 36 days, 43 days, 50 days, 57 days and 64 days.

FIG. 5 is a graphic representation of an in vitro release of clonidinefrom three pellet doses as measured by percentage release and microgramsreleased.

FIG. 6 is a graphic representation of the calculated daily release ofclonidine from three pellet doses as measured by micrograms released.

FIG. 7 is a graphic representation of clonidine HCl animal studyformulations as measured by the cumulative clonidine releasedpercentage.

FIG. 8 is a graphic representation of clonidine HCl release for variousformulations as measured by the cumulative clonidine releasedpercentage.

FIG. 9 is a graphic representation of the cumulative in vitro releaseprofile for certain clonidine formulations.

FIG. 10 is a graphic representation of the cumulative release profilesfor certain irradiated clonidine HCl formulations.

FIG. 11 is a graphic representation of certain calculated daily releasemeasurements of clonidine from 2/3/4 pellets doses.

FIG. 12 is a graphic representation of the calculated daily release ofclonidine from certain three pellet doses.

FIG. 13 is a graphic representation of the calculated daily release ofclonidine from certain 2/3 pellet dose coaxial formulations.

FIG. 14 is a graphic representation of the cumulative in vitro releaseprofile for certain irradiated clonidine formulations.

FIG. 15 is a graphic representation of the calculated daily release ofclonidine for certain three pellet dose formulations.

FIG. 16 is a graphic representation of the micrograms of clonidinereleased for certain three pellet dose formulations.

FIG. 17 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 18 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 19 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 20 is a graphic representation of the cumulative release percentageof clonidine for one formulation.

FIG. 21 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 22 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 23 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 24 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 25 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 26 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 27 is a graphic representation of the cumulative elution percentageof clonidine for one formulation.

FIG. 28 is a graphic representation of the cumulative release percentageof clonidine for one formulation.

FIG. 29 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 30 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations.

FIG. 31 is a graphic representation of the cumulative elution percentageof clonidine for one formulation.

FIG. 32 is a graphic representation of the cumulative release percentageof clonidine for certain formulations.

FIG. 33 is a graphic representation of the cumulative release percentageof clonidine for one formulation.

FIG. 34 is a graphic representation of the cumulative release percentageof clonidine for one formulation.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding the numerical ranges and parameters set forth herein,the broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

The headings below are not meant to limit the disclosure in any way;embodiments under any one heading may be used in conjunction withembodiments under any other heading.

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a drug depot” includes one, two, three or more drugdepots.

The abbreviation “DLG” refers to poly(DL-lactide-co-glycolide).

The abbreviation “DL” refers to poly(DL-lactide).

The abbreviation “LG” refers to poly(L-lactide-co-glycolide).

The abbreviation “CL” refers to polycaprolactone.

The abbreviation “DLCL” refers to poly(DL-lactide-co-caprolactone).

The abbreviation “LCL” refers to poly(L-lactide-co-caprolactone).

The abbreviation “G” refers to polyglycolide.

The abbreviation “PEG” refers to poly(ethylene glycol).

The abbreviation “PLGA” refers to poly(lactide-co-glycolide) also knownas poly(lactic-co-glycolic acid), which are used interchangeably.

The abbreviation “PLA” refers to polylactide.

The abbreviation “POE” refers to poly(orthoester).

New compositions and methods are provided that effectively reduce,prevent or treat degenerative disc disease. In various embodiments,alpha adrenergic receptor agonist compositions and methods are providedthat reduce the size of the herniation in a single drug depot ormultiple drug depots. New alpha adrenergic agonist compositions andmethods are provided, which can easily allow accurate and preciseimplantation of a drug depot containing the alpha adrenergic receptoragonist with minimal physical and psychological trauma to a patient. Oneadvantage of the alpha adrenergic agonist drug depot compositions andmethods is that the drug depot can now be easily delivered to the targettissue site (e.g., at the nucleus pulposus, or near the spinal column,etc.) and reduce, prevent or treat the intervertebral disc herniation.In this way, accurate and precise implantation of the drug depot in aminimally invasive procedure to treat the disc herniation can beaccomplished.

Alpha-Adrenergic Agonists

The methods and compositions of the present application utilize an alphaadrenergic agonist. Human adrenergic receptors are integral membraneproteins, which have been classified into two broad classes, the alphaand the beta adrenergic receptors.

Both types mediate the action of the peripheral sympathetic nervoussystem upon binding of catecholamines, norepinephrine and epinephrine.Norepinephrine is produced by adrenergic nerve endings, whileepinephrine is produced by the adrenal medulla. The binding affinity ofadrenergic receptors for these compounds forms one basis of theclassification: alpha receptors tend to bind norepinephrine morestrongly than epinephrine and much more strongly than the syntheticcompound isoproterenol. The preferred binding affinity of these hormonesis reversed for the beta receptors. In many tissues, the functionalresponses, such as smooth muscle contraction, induced by alpha receptoractivation are opposed to responses induced by beta receptor binding.

Subsequently, the functional distinction between alpha and betareceptors was further highlighted and refined by the pharmacologicalcharacterization of these receptors from various animal and tissuesources. As a result, alpha and beta adrenergic receptors were furthersubdivided into alpha-1, alpha-2, alpha-1/alpha-2 subtypes. Functionaldifferences between alpha-1 and alpha-2 receptors have been recognized,and compounds, which exhibit selective binding between these twosubtypes have been developed. Thus, in published international patentapplication WO 92/0073, the selective ability of the R(+) enantiomer ofterazosin to selectively bind to adrenergic receptors of the alpha-1subtype was reported. The alpha-1/alpha-2 selectivity of this compoundwas disclosed as being significant because agonist stimulation of thealpha-2 receptors was said to inhibit secretion of epinephrine andnorepinephrine, while antagonism of the alpha-2 receptor was said toincrease secretion of these hormones. For a further general backgroundon the alpha-adrenergic receptors, the reader's attention is directed totext known in the art such as for example Robert R. Ruffolo, Jr.,alpha-Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology,(Progress in Basic and Clinical Pharmacology series, Karger, 1991). Thecloning, sequencing and expression of alpha receptor subtypes fromanimal tissues has led to the subclassification of the alpha-1adrenergic receptors into alpha-1A, alpha-1B, and alpha-1D. Similarly,the alpha-2 adrenergic receptors have also been classified alpha-2A,alpha-2B, and alpha-2C receptors based on their pharmacological andmolecular characterization: alpha-2A/D (alpha-2A in human and alpha-2Din rat); alpha-2B; and alpha-2C (Bylund et al., Pharmacol. Rev.46:121-136 (1994); and Hein and Kobilka, Neuropharmacol. 357-366(1995)). The alpha-2A and alpha-2B subtypes can regulate arterialcontraction in some vascular beds, and the alpha-2A and alpha-2Csubtypes mediate feedback inhibition of norepinephrine release fromsympathetic nerve endings. The alpha-2A subtype also mediates many ofthe central effects of alpha-2 adrenergic agonists (Calzada andArtinano, Pharmacol. Res. 44: 195-208 (2001); Hein et al., Ann. NY Acad.Science 881:265-271 (1999). Each alpha-2 receptor subtype appears toexhibit its own pharmacological and tissue specificities. Compoundshaving a degree of specificity for one or more of these subtypes may bemore specific therapeutic agents for a given indication than, forexample, an alpha-2 receptor pan-agonist (such as the drug clonidine).

The term “alpha adrenergic agonist” as used herein, refers to anycompound that binds to and/or activates and/or agonizes at least one ormore alpha-adrenergic receptor or its subtypes to any degree and/orstabilizes at least one or more alpha-adrenergic receptor or itssubtypes in an active or inactive conformation. Thus, by the termalpha-adrenergic receptor agonist it is meant to include partialagonists, inverse agonists, as well as complete agonists of one or morealpha-adrenergic receptors or its subtypes.

The terms “alpha adrenergic receptor agonist” “alpha adrenergic agonist”and “alpha agonist” as used herein, are synonymous. An alpha adrenergicagonist may be a selective alpha-1 adrenergic agonist, a selectivealpha-2 adrenergic agonist, or a mixed alpha-1/alpha-2 adrenergicagonist. The term “mixed alpha-1/alpha-2 agonist” as used herein, refersto a drug that activates both the alpha-1 receptor and the alpha-2receptor including one or more of its subtypes. It may also be referredto as a non-selective alpha agonist.

It will be understood by those of ordinary skill in the art thatselective alpha-2 agonists may weakly activate the alpha-1 receptor andthe alpha-1 agonist may weakly activate the alpha-2 receptor but thisweak activation will not be to any significant amount and thus thecompound is still classified as a selective alpha-1 or alpha-2 agonist.

The term “activate” or grammatical variants thereof, as used herein,refers to binding to a receptor and causing the receptor to produce acellular or physiological change. Agonist activation can becharacterized using any of a variety of routine assays, including, forexample, Receptor Selection and Amplification Technology (RSAT) assays(Messier et al., Pharmacol. Toxicol. 76:308-11 (1995); cyclic AMP assays(Shimizu et al., J. Neurochem. 16:1609-1619 (1969)); and cytosensormicrophysiometry assays (Neve et al., J. Biol. Chem. 267:25748-25753(1992)). For example, such assays generally are performed using cellsthat naturally express only a single alpha adrenergic receptor subtype,or using transfected cells expressing a single recombinantalpha-adrenergic receptor subtype. The adrenergic receptor can be ahuman receptor or homolog of a human receptor having a similarpharmacology. The RSAT assay measures receptor-mediated loss of contactinhibition resulting in selective proliferation of receptor-containingcells in a mixed population of confluent cells. The increase in cellnumber is assessed with an appropriate detectable marker gene such asbeta-galactosidase, if desired, in a high throughput or ultra highthroughput assay format. Receptors that activate the G protein, Gq,elicit the proliferative response. Alpha-adrenergic receptors, whichnormally couple to Gi, activate the RSAT response when coexpressed witha hybrid Gq protein containing a Gi receptor recognition domain,designated Gq/i5 (Conklin et al., Nature 363:274-6 (1993)).

In some embodiments, the alpha adrenergic receptor agonist comprises analpha-1 adrenergic receptor agonist, which acts as an analgesic and/oranti-inflammatory agent. Alpha 1-adrenergic receptors are members of theG protein-coupled receptor superfamily. Upon activation, aheterotrimeric G protein, Gq, activates phospholipase C (PLC), whichcauses an increase in IP3 and calcium. This triggers the physiologicaleffects. Examples of alpha-1 adrenergic receptor agonists include, butare in no way limited to methoxamine, methylnorepinephrine,norepinephrine, metaraminol, oxymetazoline, phenylephrine,2-(anilinomethyl)imidazolines, synephrine, or a combination thereof.

In some embodiments, the alpha adrenergic receptor agonist comprises analpha-2 adrenergic receptor agonist, which acts as an analgesic and/oranti-inflammatory agent. Examples of alpha-2 adrenergic receptoragonists useful in the present application include, but are in no waylimited to L-norepinephrine, clonidine, dexmetdetomidine, apraclonidine,methyldopa, tizanidine, brimonidine, xylometazoline, tizanidine,tetrahydrozoline, oxymetazoline, guanfacine, guanabenz, guanoxabenz,guanethidine, xylazine, moxonidine, mivazerol, medetomide, rilmenidine,UK 14,304, B-HT 933, B-HT 920, octopamine or a combination thereof.

Other alpha adrenergic agonists include, but are not limited to,amidephrine, amitraz, anisodamine, apraclonidine, cirazoline,detomidine, epinephrine, ergotamine, etilefrine, indanidine, lofexidine,medetomidine, mephentermine, metaraminol, methoxamine, midodrine,naphazoline, norepinephrine, norfenefrine, octopamine, oxymetazoline,phenylpropanolamine, rilmenidine, romifidine, synephrine, talipexole,tizanidine, or a combination thereof.

In one embodiment, the alpha adrenergic agonist can be used as a racemicmixture. In yet another embodiment, the alpha adrenergic agonist is usedas a single stereoisomer. In another embodiment, the alpha adrenergicagonist is used as a mixture of stereo isomers containing equal (1:1) orunequal amounts of stereoisomers. For example, in some embodiments, thealpha adrenergic agonist may comprise mixtures of (+)R and (−)Senantiomers of the agonist. In various embodiments, the alpha adrenergicagonist may comprise a 1:1 racemic mixture of the agonist.

The target tissue site chosen for alpha-agonist delivery depends on,among other things, upon the condition being treated, desiredtherapeutic concentration of the drug to be achieved in the patient andthe duration of drug concentration that must be maintained.

In some embodiments, local administration of the drug depot at or nearthe target tissue site (e.g., degenerative disc) allows for a lower doseof the alpha adrenergic agonist to be used than the usual oral,intravenous, or intramuscular dose. For example, local administration ofthe drug depot can be accomplished with daily doses that are 20%, 15%,10%, 5%, 1%, 0.5%, 0.1%, 0.01% of the usual oral, intravenous orintramuscular dose. In turn, systemic side effects, such as for example,liver transaminase elevations, hepatitis, liver failure, myopathy,constipation, etc. may be reduced or eliminated.

The concentration of alpha adrenergic receptor agonist (e.g., alpha-1,alpha-2, alpha-1 and alpha-2) included in the drug depot and used in themethodologies described herein is a concentration effective to produce atherapeutic effect of preventing, treating or reducing pain and/orinflammation. Dosages of alpha adrenergic receptor agonist, e.g.,clonidine for producing an analgesic effect in human patients upon localadministration can typically range in some embodiments from betweenabout 150 micrograms to 800 micrograms per day or from 3-12micrograms/hour by local infusion.

However, as will be understood by the skilled artisan upon reading thisdisclosure, the effective concentration will vary depending upon thealpha adrenergic receptor agonist selected, the route of administration,the frequency of administration, the formulation administered, and thecondition being treated.

In one embodiment, the alpha adrenergic agonist is administered in anamount of about 0.0001 mg/kg/day to about 40 mg/kg/day for reducing,preventing or treating pain and/or inflammation from degenerative discdisease. In another embodiment, the alpha adrenergic agonist isadministered in an amount of about 0.001 mg/kg/day to about 4 mg/kg/day.In one embodiment, the alpha adrenergic agonist is administered in anamount of about 0.01 mg/kg/day to about 0.4 mg/kg/day.

In one embodiment, the one or more alpha adrenergic agonists can beadministered in a drug depot, which also contains anotheranti-inflammatory and/or an analgesic. By including one or more alphaadrenergic agonists in the drug depot, this can enhance the effect ofthe analgesic and/or anti-inflammatory. In one embodiment, “enhancedeffect” means that, when co-administered with an alpha adrenergicagonist, lower doses of the selected analgesic and/or anti-inflammatoryagent may be required to achieve the same analgesic effect as when theanalgesic and/or anti-inflammatory is administered alone or greateranalgesic or anti-inflammatory effect is achieved when usual doses ofthe selected analgesic and/or anti-inflammatory is administered with analpha adrenergic agonist.

Analgesic refers to an agent or compound that can reduce, relieve oreliminate pain. In addition to the alpha adrenergic agonist, examples ofanalgesic agents include but are not limited to acetaminophen, a localanesthetic, such as for example, lidocaine, bupivicaine, ropivacaine,opioid analgesics such as buprenorphine, butorphanol, dextromoramide,dezocine, dextropropoxyphene, diamorphine, fentanyl, alfentanil,sufentanil, hydrocodone, hydromorphone, ketobemidone, levomethadyl,levorphanol, mepiridine, methadone, morphine, nalbuphine, opium,oxycodone, papaveretum, pentazocine, pethidine, phenoperidine,piritramide, dextropropoxyphene, remifentanil, sufentanil, tilidine,tramadol, codeine, dihydrocodeine, meptazinol, dezocine, eptazocine,flupirtine or a combination thereof.

The phrase “anti-inflammatory agent” refers to an agent or compound thathas anti-inflammatory effects. These agents may remedy pain by reducinginflammation. In addition to the alpha adrenergic agonist, examples ofanti-inflammatory agents include, but are not limited to, a statin,sulindac, sulfasalazine, guanidinoethyldisulfide, naroxyn, diclofenac,indomethacin, ibuprofen, flurbiprofen, ketoprofen, aclofenac, aloxiprin,aproxen, aspirin, diflunisal, fenoprofen, mefenamic acid, naproxen,phenylbutazone, piroxicam, meloxicam, salicylamide, salicylic acid,desoxysulindac, tenoxicam, ketoralac, flufenisal, salsalate,triethanolamine salicylate, aminopyrine, antipyrine, oxyphenbutazone,apazone, cintazone, flufenamic acid, clonixeril, clonixin, meclofenamicacid, flunixin, colchicine, demecolcine, allopurinol, oxypurinol,benzydamine hydrochloride, dimefadane, indoxole, intrazole, mimbanehydrochloride, paranylene hydrochloride, tetrydamine, benzindopyrinehydrochloride, fluprofen, ibufenac, naproxol, fenbufen, cinchophen,diflumidone sodium, fenamole, flutiazin, metazamide, letimidehydrochloride, nexeridine hydrochloride, octazamide, molinazole,neocinchophen, nimazole, proxazole citrate, tesicam, tesimide, tolmetin,triflumidate, fenamates (mefenamic acid, meclofenamic acid), nabumetone,celecoxib, etodolac, nimesulide, apazone, gold, tepoxalin;dithiocarbamate, or a combination thereof. Anti-inflammatory agents alsoinclude other compounds such as steroids, such as for example,fluocinolone, cortisol, cortisone, hydrocortisone, fludrocortisone,prednisone, prednisolone, methylprednisolone, triamcinolone,betamethasone, dexamethasone, beclomethasone, fluocinolone, fluticasoneinterleukin-1 receptor antagonists, thalidomide (a TNF-α releaseinhibitor), thalidomide analogues (which reduce TNF-α production bymacrophages), bone morphogenetic protein (BMP) type 2 or BMP-4(inhibitors of caspase 8, a TNF-α activator), quinapril (an inhibitor ofangiotensin II, which upregulates TNF-α), interferons such as IL-11(which modulate TNF-α receptor expression), and aurin-tricarboxylic acid(which inhibits TNF-α), guanidinoethyldisulfide, or a combinationthereof.

Exemplary anti-inflammatory agents include, for example, naproxen;diclofenac; celecoxib; sulindac; diflunisal; piroxicam; indomethacin;etodolac; meloxicam; ibuprofen; ketoprofen; r-flurbiprofen; mefenamic;nabumetone; sulfasalazine, sulindac, tolmetin, and sodium salts of eachof the foregoing; ketorolac bromethamine; ketorolac tromethamine;ketorolac acid; choline magnesium trisalicylate; rofecoxib; valdecoxib;lumiracoxib; etoricoxib; aspirin; salicylic acid and its sodium salt;salicylate esters of alpha, beta, gamma-tocopherols and tocotrienols(and all their d, 1, and racemic isomers); methyl, ethyl, propyl,isopropyl, n-butyl, sec-butyl, t-butyl, esters of acetylsalicylic acid;tenoxicam; aceclofenac; nimesulide; nepafenac; amfenac; bromfenac;flufenamate; phenylbutazone, or a combination thereof.

Exemplary steroids include, for example, 21-acetoxypregnenolone,alclometasone, algestone, amcinonide, beclomethasone, betamethasone,budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone,cloprednol, corticosterone, cortisone, cortivazol, deflazacort,desonide, desoximetasone, dexamethasone, dexamethasone 21-acetate,dexamethasone 21-phosphate di-Na salt, diflorasone, diflucortolone,difluprednate, enoxolone, fluazacort, flucloronide, flumethasone,flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl,fluocortolone, fluorometholone, fluperolone acetate, fluprednideneacetate, fluprednisolone, flurandrenolide, fluticasone propionate,formocortal, halcinonide, halobetasol propionate, halometasone,halopredone acetate, hydrocortamate, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone,mometasone furoate, paramethasone, prednicarbate, prednisolone,prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate,prednisone, prednival, prednylidene, rimexolone, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide,triamcinolone hexacetonide or a combination thereof.

Examples of a useful statin that can be included in the depot fortreatment of pain and/or inflammation include, but is not limited to,atorvastatin, simvastatin, pravastatin, cerivastatin, mevastatin (seeU.S. Pat. No. 3,883,140, the entire disclosure is herein incorporated byreference), velostatin (also called synvinolin; see U.S. Pat. Nos.4,448,784 and 4,450,171 these entire disclosures are herein incorporatedby reference), fluvastatin, lovastatin, rosuvastatin and fluindostatin(Sandoz XU-62-320), dalvastain (EP Appln. Publn. No. 738510 A2, theentire disclosure is herein incorporated by reference), eptastatin,pitavastatin, or pharmaceutically acceptable salts thereof or acombination thereof. In various embodiments, the statin may comprisemixtures of (+)R and (−)-S enantiomers of the statin. In variousembodiments, the statin may comprise a 1:1 racemic mixture of thestatin.

Anti-inflammatory agents also include those with anti-inflammatoryproperties, such as, for example, amitriptyline, carbamazepine,gabapentin, pregabalin, clonidine, or a combination thereof.

Unless otherwise specified or apparent from context, where thisspecification and the set of claims that follows refer to an alphaadrenergic receptor agonist or alpha agonist (e.g., alpha-2 agonist,alpha-2 selective agonist, alpha-1 selective agonist, alpha-1/alpha-2mixed or non-selective agonist, etc.), the inventor is also referring toa pharmaceutically acceptable salt of the alpha adrenergic receptoragonist including stereoisomers. Pharmaceutically acceptable saltsinclude those salt-forming acids and bases that do not substantiallyincrease the toxicity of the compound. Some examples of potentiallysuitable salts include salts of alkali metals such as magnesium,calcium, sodium, potassium and ammonium, salts of mineral acids such ashydrochloric, hydriodic, hydrobromic, phosphoric, metaphosphoric, nitricand sulfuric acids, as well as salts of organic acids such as tartaric,acetic, citric, malic, benzoic, glycollic, gluconic, gulonic, succinic,arylsulfonic, e.g., p-toluenesulfonic acids, or the like.

A “drug depot” is the composition in which at least one alpha adrenergicreceptor agonist is administered to the body. Thus, a drug depot maycomprise a physical structure to facilitate implantation and retentionin a desired site (e.g., a disc space, a spinal canal, a tissue of thepatient, particularly at or near a site of surgery, or other site ofinflammation, etc.). The drug depot also comprises the drug itself. Theterm “drug” as used herein is generally meant to refer to any substancethat alters the physiology of a patient. The term “drug” may be usedinterchangeably herein with the terms “therapeutic agent,”“therapeutically effective amount,” and “active pharmaceuticalingredient” or “API.” It will be understood that unless otherwisespecified a “drug” formulation may include more than one therapeuticagent, wherein exemplary combinations of therapeutic agents include acombination of two or more drugs. The drug provides a concentrationgradient of the therapeutic agent for delivery to the site. In variousembodiments, the drug depot provides an optimal drug concentrationgradient of the therapeutic agent at a distance of up to about 0.1 mm toabout 5 cm from the implant site, and comprises at least one alphaadrenergic receptor agonist or its pharmaceutically acceptable salt.

A “depot” includes but is not limited to capsules, microspheres,microparticles, microcapsules, microfibers particles, nanospheres,nanoparticles, coating, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, gels, fiber, strip, sheet or other pharmaceuticaldelivery compositions or a combination thereof. The drug depot maycomprise a pump that holds and administers the pharmaceutical. In someembodiments, the drug depot has pores that allow release of the drugfrom the depot. The drug depot will allow fluid in the depot to displacethe drug. However, cell infiltration into the depot will be prevented bythe size of the pores of the depot. In this way, in some embodiments,the depot should not function as a tissue scaffold and allow tissuegrowth. Rather, the drug depot will solely be utilized for drugdelivery. In some embodiments, the pores in the drug depot will be lessthan 250 to 500 microns. This pore size will prevent cells frominfiltrating the drug depot and laying down scaffolding cells. Thus, inthis embodiment, drug will elute from the drug depot as fluid enters thedrug depot, but cells will be prevented from entering. In someembodiments, where there are little or no pores, the drug will elute outfrom the drug depot by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body.

Suitable materials for the depot are ideally pharmaceutically acceptablebiodegradable and/or any bioabsorbable materials that are preferably FDAapproved or GRAS materials. These materials can be polymeric ornon-polymeric, as well as synthetic or naturally occurring, or acombination thereof. In various embodiments, the drug depot may not bebiodegradable or comprise material that is not biodegradable.Non-biodegradable polymers include, but are not limited to, variouscellulose derivatives (carboxymethyl cellulose, cellulose acetate,cellulose acetate propionate, ethyl cellulose, hydroxypropyl methylcellulose, hydroxyalkyl methyl celluloses, and alkyl celluloses),silicon and silicon-based polymers (such as polydimethylsiloxane),polyethylene-co-(vinyl acetate), poloxamer, polyvinylpyrrolidone,poloxamine, polypropylene, polyamide, polyacetal, polyester, polyethylene-chlorotrifluoroethylene, polytetrafluoroethylene (PTFE or“Teflon™”), styrene butadiene rubber, polyethylene, polypropylene,polyphenylene oxide-polystyrene, poly-α-chloro-p-xylene,polymethylpentene, polysulfone, non-degradable ethylene-vinyl acetate(e.g., ethylene vinyl acetate disks and poly(ethylene-co-vinylacetate)), and other related biostable polymers or combinations thereof.

In some embodiments, the drug depot comprises at least one biodegradablematerial in a wt % of about 99.5%, 99%, 98%, 97%, 96%, 95%, 94%, 93%,92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%,78%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 65%, 60%, 55%, 50%, 45%, 35%,25%, 20%, 15%, 10%, or 5% based on total weight of the depot and theremainder is active and/or inactive pharmaceutical ingredients.

In some embodiments, the loading of alpha agonist in the drug depot isfrom about 0.5 wt % to about 30 wt. %, or about 1 wt. % to about 20 wt.%. In some embodiments, the loading is from about 10 wt. % to about 20wt. %.

The drug depot may comprise non-resorbable polymers as well. Thesenon-resorbable polymers can include, but are not limited to, delrin,polyurethane, copolymers of silicone and polyurethane, polyolefins (suchas polyisobutylene and polyisoprene), acrylamides (such as polyacrylicacid and poly(acrylonitrile-acrylic acid)), neoprene, nitrile, acrylates(such as polyacrylates, poly(2-hydroxy ethyl methacrylate), methylmethacrylate, 2-hydroxyethyl methacrylate, and copolymers of acrylateswith N-vinyl pyrrolidone), N-vinyl lactams, polyacrylonitrile,glucomannan gel, vulcanized rubber and combinations thereof. Examples ofpolyurethanes include thermoplastic polyurethanes, aliphaticpolyurethanes, segmented polyurethanes, hydrophilic polyurethanes,polyether-urethane, polycarbonate-urethane and siliconepolyether-urethane. Typically, the non-degradable drug depots may needto be removed.

A “therapeutically effective amount” or “effective amount” is such thatwhen administered, the drug results in alteration of the biologicalactivity, such as, for example, inhibition of inflammation, reduction oralleviation of pain, improvement in the degenerative disc disease, etc.The dosage administered to a patient can unless otherwise specified orapparent from context be as single or multiple doses depending upon avariety of factors, including the drug's administered pharmacokineticproperties, the route of administration, patient conditions andcharacteristics (sex, age, body weight, health, size, etc.), extent ofsymptoms, concurrent treatments, frequency of treatment and the effectdesired. In some embodiments the formulation is designed for immediaterelease. In other embodiments the formulation is designed for sustainedrelease. In other embodiments, the formulation comprises one or moreimmediate release surfaces and one or more sustain release surfaces.

The phrases “sustained release” or “sustain release” (also referred toas extended release or controlled release) are used herein to refer toone or more therapeutic agent(s) that is introduced into the body of ahuman or other mammal and continuously or continually releases a streamof one or more therapeutic agents over a predetermined time period andat a therapeutic level sufficient to achieve a desired therapeuticeffect throughout the predetermined time period. Reference to acontinuous or continual release stream is intended to encompass releasethat occurs as the result of biodegradation in vivo of the drug depot,or a matrix or component thereof, or as the result of metabolictransformation or dissolution of the therapeutic agent(s) or conjugatesof therapeutic agent(s). As persons of ordinary skill are aware,sustained release formulations may, by way of example, be created asfilms, slabs, sheets, pellets, microparticles, microspheres,microcapsules, spheroids, shaped derivatives or paste. The formulationsmay be in a form that is suitable for suspension in isotonic saline,physiological buffer or other solution acceptable for injection into apatient. Further, the formulations may be used in conjunction with anyimplantable, insertable or injectable system that a person of ordinaryskill would appreciate as useful in connection with embodiments hereinincluding but not limited to parenteral formulations, microspheres,microcapsules, gels, pastes, implantable rods, pellets, plates orfibers, etc.

The phrase “immediate release” is used herein to refer to one or moretherapeutic agent(s) that is introduced into the body and that isallowed to dissolve in or become absorbed at the location to which it isadministered, with no intention of delaying or prolonging thedissolution or absorption of the drug. Immediate release refers to therelease of drug within a short time period following administration,e.g., generally within a few minutes to about 1 hour.

The term “mammal” refers to organisms from the taxonomy class“mammalian,” including but not limited to humans, other primates such aschimpanzees, apes, orangutans and monkeys, rats, mice, cats, dogs, cows,horses, etc. In various embodiments, the mammal is a human patient.

The phrase “release rate profile” refers to the percentage of activeingredient that is released over fixed units of time, e.g., mcg/hr,mcg/day, mg/hr, mg/day, 10% per day for ten days, etc. As persons ofordinary skill know, a release rate profile may be but need not belinear. By way of a non-limiting example, the drug depot may be a pelletthat releases at least one alpha agonist over a period of time.

Treating or treatment of a disease or condition refers to executing aprotocol, which may include administering one or more drugs to a patient(human, normal or otherwise, or other mammal), in an effort to alleviatesigns or symptoms of the disease. Alleviation can occur prior to signsor symptoms of the disease or condition appearing, as well as aftertheir appearance. Thus, “treating” or “treatment” includes “preventing”or “prevention” of disease or undesirable condition. In addition,“treating” or “treatment” does not require complete alleviation of signsor symptoms, does not require a cure, and specifically includesprotocols that have only a marginal effect on the patient. “Reducingpain and/or inflammation” includes a decrease in pain and/orinflammation and does not require complete alleviation of pain and/orinflammation signs or symptoms, and does not require a cure. In variousembodiments, reducing pain and/or inflammation includes even a marginaldecrease in pain and/or inflammation. By way of example, theadministration of the effective dosage alpha adrenergic receptor agonistmay be used to prevent, treat or relieve the symptoms of pain and/orinflammation for different diseases or conditions. Thesedisease/conditions may comprise oral-facial diseases, bursitis,tendonitis, chronic inflammatory diseases, including, but not limited toautoimmune diseases, such as multiple sclerosis, degenerative discdisease, rheumatoid arthritis, osteoarthritis, insulin dependentdiabetes (type I diabetes), systemic lupus erythrematosis and psoriasis,immune pathologies induced by infectious agents, such as helminthic(e.g., leishmaniasis) and certain viral infections, including HIV, andbacterial infections, including Lyme disease, tuberculosis andlepromatous leprosy, tissue transplant rejection, graft versus hostdisease and atopic conditions, such as asthma and allergy, includingallergic rhinitis, gastrointestinal allergies, including food allergies,eosinophilia, conjunctivitis or glomerular nephritis.

One chronic condition is sciatica. In general, sciatica” is an exampleof pain that can transition from acute to neuropathic pain. Sciaticarefers to pain associated with the sciatic nerve which runs from thelower part of the spinal cord (the lumbar region), down the back of theleg and to the foot. Sciatica generally begins with a herniated disc.The herniated disc itself leads to local immune system activation. Theherniated disc also may damage the nerve root by pinching or compressingit, leading to additional immune system activation in the area. Invarious embodiments, the alpha adrenergic agonist may be used to reduce,treat, or prevent sciatic pain and/or inflammation by locallyadministering the alpha adrenergic agonist at one or more target tissuesites (e.g., nerve root, dorsal root ganglion, focal sites of pain, ator near the spinal column, etc.).

“Localized” delivery includes delivery where one or more drugs aredeposited within a tissue, for example, a nerve root of the nervoussystem or a region of the brain, or in close proximity (within about 10cm, or within about 5 cm, or within 0.1 cm for example) thereto. A“targeted delivery system” provides delivery of one or more drugsdepots, gels or depot dispersed in the gel having a quantity oftherapeutic agent that can be deposited at or near the target site asneeded for treatment of pain, inflammation or other disease orcondition.

The term “biodegradable” includes that all or parts of the drug depotwill degrade over time by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body. In variousembodiments, “biodegradable” includes that the depot (e.g.,microparticle, microsphere, etc.) can break down or degrade within thebody to non-toxic components after or while a therapeutic agent has beenor is being released. By “bioerodible” it is meant that the depot willerode or degrade over time due, at least in part, to contact withsubstances found in the surrounding tissue, fluids or by cellularaction. By “bioabsorbable” it is meant that the depot will be brokendown and absorbed within the human body, for example, by a cell ortissue. “Biocompatible” means that the depot will not cause substantialtissue irritation or necrosis at the target tissue site.

The phrase “pain management medication” includes one or more therapeuticagents that are administered to prevent, alleviate or remove painentirely. These include one or more alpha adrenergic agonists alone orin combination with an anti-inflammatory agent, muscle relaxant,analgesic, anesthetic, narcotic, or so forth, or combinations thereof.

In various embodiments, the depot can be designed to cause an initialburst dose of therapeutic agent within the first 24 hours, 2 days, 3days, 4 days, or 5 days after implantation. “Initial burst” or “bursteffect” or “bolus dose” refer to the release of therapeutic agent fromthe depot during the first 24 hours, 2 days, 3 days, 4 days, or 5 daysafter the depot comes in contact with an aqueous fluid (e.g., cerebralspinal fluid, blood, etc.). This burst effect is particularly beneficialfor the analgesic, while in various embodiments, for theanti-inflammatory agent a more linear release of a longer duration maybe desired. The “burst effect” is believed to be due to the increasedrelease of therapeutic agent from the depot. In alternative embodiments,the depot (e.g., gel, pellet, wafer, etc.) is designed to avoid thisinitial burst effect (e.g., by applying an outer polymer coating to thedepot).

The drug depot comprising at least one alpha-2 adrenergic agonist or itspharmaceutically acceptable salt may be co-administered with a musclerelaxant. Co-administration may involve administering at the same timein separate drug depots or formulating together in the same drug depot.

Exemplary muscle relaxants include by way of example and not limitation,alcuronium chloride, atracurium bescylate, baclofen, carbolonium,carisoprodol, chlorphenesin carbamate, chlorzoxazone, cyclobenzaprine,dantrolene, decamethonium bromide, fazadinium, gallamine triethiodide,hexafluorenium, meladrazine, mephensin, metaxalone, methocarbamol,metocurine iodide, pancuronium, pridinol mesylate, styramate,suxamethonium, suxethonium, thiocolchicoside, tizanidine, tolperisone,tubocuarine, vecuronium, or combinations thereof.

The drug depot may also comprise other therapeutic agents or activeingredients in addition to the at least one alpha adrenergic agonist orits pharmaceutically acceptable salt. Suitable additional therapeuticagents include, but are not limited to, integrin antagonists, alpha-4beta-7 integrin antagonists, cell adhesion inhibitors, interferon gammaantagonists, CTLA4-Ig agonists/antagonists (BMS-188667), CD40 ligandantagonists, Humanized anti-IL-6 mAb (MRA, Tocilizumab, Chugai), HMGB-1mAb (Critical Therapeutics Inc.), anti-IL2R antibodies (daclizumab,basilicimab), ABX (anti IL-8 antibodies), recombinant human IL-10, orHuMax IL-15 (anti-IL 15 antibodies).

Other suitable therapeutic agents that may be co-administered with thealpha adrenergic agonist include IL-1 inhibitors, such Kineret®(anakinra) which is a recombinant, non-glycosylated form of the humaninerleukin-1 receptor antagonist (IL-IRa), or AMG 108, which is amonoclonal antibody that blocks the action of IL-1. Therapeutic agentsalso include excitatory amino acids such as glutamate and aspartate,antagonists or inhibitors of glutamate binding to NMDA receptors, AMPAreceptors, and/or kainate receptors. It is contemplated that wheredesirable a pegylated form of the above may be used. Examples of othertherapeutic agents include NF kappa B inhibitors such asglucocorticoids, or antioxidants, such as dilhiocarbamate.

Specific examples of additional therapeutic agents suitable for useinclude, but are not limited to, an anabolic growth factor oranti-catabolic growth factor, or an osteoinductive growth factor or acombination thereof.

Suitable anabolic growth or anti-catabolic growth factors include, butare not limited to, a bone morphogenetic protein, a growthdifferentiation factor, a LIM mineralization protein, CDMP or progenitorcells or a combination thereof.

In addition to the alpha agonist, suitable analgesic agents include, butare not limited to, acetaminophen, bupivacaine, tramadol, opioidanalgesics such as amitriptyline, carbamazepine, gabapentin, pregabalin,opioid analgesics or a combination thereof. Opioid analgesics include,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium,oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone,phenomorphan, phenazocine, phenoperidine, piminodine, piritramide,propheptazine, promedol, properidine, propoxyphene, sufentanil,tilidine, tramadol or a combination thereof.

For each alpha adrenergic agonist, in some embodiments, the release ofeach compound may be for at least one, at least two, at least three, atleast four, at least five, at least six, at least seven, at least eight,at least nine, at least ten, at least eleven, at least twelve, at leastthirteen, at least fourteen, or at least fifteen days, or longer.

The therapeutic agent (e.g., alpha agonist, muscle relaxant, steroid,etc.) also includes its pharmaceutically acceptable salt. As usedherein, “pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds (e.g., esters or amines) wherein the parent compoundmay be modified by making acidic or basic salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,or nitric acids; or the salts prepared from organic acids such asacetic, fuoric, propionic, succinic, glycolic, stearic, lactic, malic,tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,tolunesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionicacid. Pharmaceutically acceptable also includes the racemic mixtures((+)-R and (−)-S enantiomers) or each of the dextro and levo isomers ofthe therapeutic agent individually. The therapeutic agent may be in thefree acid or base form or be pegylated for long acting activity.

Clonidine

In some embodiments, the alpha adrenergic receptor agonist is clonidine.When referring to clonidine, unless otherwise specified or apparent fromcontext it is understood that the inventor is also referring topharmaceutically acceptable salts. One well-known commercially availablesalt for clonidine is its hydrochloride salt. Some other examples ofpotentially pharmaceutically acceptable salts include those salt-formingacids and bases that do not substantially increase the toxicity of acompound, such as, salts of alkali metals such as magnesium, potassiumand ammonium, salts of mineral acids such as hydriodic, hydrobromic,phosphoric, metaphosphoric, nitric and sulfuric acids, as well as saltsof organic acids such as tartaric, acetic, citric, malic, benzoic,glycollic, gluconic, gulonic, succinic, arylsulfonic, e.g.,p-toluenesulfonic acids, and the like.

Further, when referring to clonidine the active ingredient may not onlybe in the salt form, but also in the base form (e.g., free base). Invarious embodiments, if it is in the base form, it may be combined withpolymers under conditions in which there is not severe polymerdegradation, as may be seen upon heat or solvent processing that mayoccur with PLGA or PLA. By way of a non limiting example, whenformulating clonidine with poly(orthoesters) it may be desirable to usethe clonidine base formulation. By contrast, when formulating clonidinewith PLGA, it may be desirable to use the HCl salt form.

In one embodiment, the alpha adrenergic agonist is an alpha-2 adrenergicagonist comprising clonidine, also referred to as2,6-dichloro-N-2-imidazolidinyldenebenzenamine. Clonidine or apharmaceutically acceptable salt thereof is available from variouspharmaceutical manufactures for reducing, preventing or treating painand/or inflammation from a degenerative disc disease.

The dosage may be from approximately 0.0005 to approximately 960 μg/day.Additional dosages of clonidine include from approximately 0.0005 toapproximately 900 μg/day; approximately 0.0005 to approximately 500μg/day; approximately 0.0005 to approximately 250 μg/day; approximately0.0005 to approximately 100 μg/day; approximately 0.0005 toapproximately 75 μg/day; approximately 0.001 to approximately 70 μg/day;approximately 0.001 to approximately 65 μg/day; approximately 0.001 toapproximately 60 μg/day; approximately 0.001 to approximately 55 μg/day;approximately 0.001 to approximately 50 μg/day; approximately 0.001 toapproximately 45 μg/day; approximately 0.001 to approximately 40 μg/day;approximately 0.001 to approximately 35 μg/day; approximately 0.0025 toapproximately 30 μg/day; approximately 0.0025 to approximately 25μg/day; approximately 0.0025 to approximately 20 μg/day; approximately0.0025 to approximately 15 μg/day; approximately 0.0025 to approximately10 μg/day; approximately 0.0025 to approximately 5 μg/day; andapproximately 0.0025 to approximately 2.5 μg/day. In another embodiment,the dosage of clonidine is from approximately 0.005 to approximately 15μg/day. In another embodiment, the dosage of clonidine is fromapproximately 0.005 to approximately 10 μg/day. In another embodiment,the dosage of clonidine is from approximately 0.005 to approximately 5μg/day. In another embodiment, the dosage of clonidine is fromapproximately 0.005 to 2.5 μg/day. In some embodiments, the amount ofclonidine is between 40 and 600 μg/day. In some embodiments, the amountof clonidine is between 200 and 400 μg/day.

In various embodiments, there is a pharmaceutical formulationcomprising: clonidine, wherein the clonidine comprises from about 0.1wt. % to about 30 wt. % of the formulation, and at least onebiodegradable polymer. In some embodiments, the pharmaceutical theclonidine comprises from about 3 wt. % to about 20 wt. %, about 3 wt. %to about 18 wt. %, about 5 wt. % to about 15 wt. % or about 7.5 wt. % toabout 12.5 wt. % of the formulation. By way of example, when using a5%-15% clonidine composition, the mole ratio of clonidine to polymerwould be from approximately 16-53 when using an approximately 80 kDaltonpolymer that has a 267 grams/mole ratio. By way of another example, whenusing a 5%-15% clonidine base in the composition, the mole ratio ofclonidine base to polymer would be from approximately 18-61 with a molemass of 230 g/mol.

In some embodiments, the at least one biodegradable polymer comprisespoly(lactic-co-glycolide) (PLGA) or poly(orthoester) (POE) or acombination thereof. The poly(lactic-co-glycolide) may comprise amixture of polyglycolide (PGA) and polylactide and in some embodiments,in the mixture, there is more polylactide than polyglycolide. In variousembodiments there is 100% polylactide and 0% polyglycolide; 95%polylactide and 5% polyglycolide; 90% polylactide and 10% polyglycolide;85% polylactide and 15% polyglycolide; 80% polylactide and 20%polyglycolide; 75% polylactide and 25% polyglycolide; 70% polylactideand 30% polyglycolide; 65% polylactide and 35% polyglycolide; 60%polylactide and 40% polyglycolide; 55% polylactide and 45%polyglycolide; 50% polylactide and 50% polyglycolide; 45% polylactideand 55% polyglycolide; 40% polylactide and 60% polyglycolide; 35%polylactide and 65% polyglycolide; 30% polylactide and 70%polyglycolide; 25% polylactide and 75% polyglycolide; 20% polylactideand 80% polyglycolide; 15% polylactide and 85% polyglycolide; 10%polylactide and 90% polyglycolide; 5% polylactide and 95% polyglycolide;and 0% polylactide and 100% polyglycolide.

In various embodiments that comprise both polylactide and polyglycolide;there is at least 95% polylactide; at least 90% polylactide; at least85% polylactide; at least 80% polylactide; at least 75% polylactide; atleast 70% polylactide; at least 65% polylactide; at least 60%polylactide; at least 55%; at least 50% polylactide; at least 45%polylactide; at least 40% polylactide; at least 35% polylactide; atleast 30% polylactide; at least 25% polylactide; at least 20%polylactide; at least 15% polylactide; at least 10% polylactide; or atleast 5% polylactide; and the remainder of the biopolymer ispolyglycolide.

In various embodiments, the drug particle size used in the drug depot isfrom about 5 to 30 micrometers, however, in various embodiments rangesfrom about 1 micron to 250 microns may be used. In some embodiments, thebiodegradable polymer comprises at least 50 wt. %, at least 60 wt. %, atleast 70 wt. %, at least 80 wt. % of the formulation, at least 85 wt. %of the formulation, at least 90 wt. % of the formulation, at least 95wt. % of the formulation or at least 97 wt. % of the formulation. Insome embodiments, the at least one biodegradable polymer and theclonidine are the only components of the pharmaceutical formulation.

In some embodiments, at least 75% of the particles have a size fromabout 10 micrometer to about 200 micrometers. In some embodiments, atleast 85% of the particles have a size from about 10 micrometer to about200 micrometers. In some embodiments, at least 95% of the particles havea size from about 10 micrometer to about 200 micrometers. In someembodiments, all of the particles have a size from about 10 micrometerto about 200 micrometers.

In some embodiments, at least 75% of the particles have a size fromabout 20 micrometer to about 180 micrometers. In some embodiments, atleast 85% of the particles have a size from about 20 micrometers toabout 180 micrometers. In some embodiments, at least 95% of theparticles have a size from about 20 micrometer to about 180 micrometers.In some embodiments, all of the particles have a size from about 20micrometer to about 180 micrometers.

In some embodiments, there is a pharmaceutical formulation comprisingthe alpha agonist clonidine, wherein the clonidine is in a mixture ofclonidine hydrochloride and clonidine base and the mixture comprisesfrom about 0.1 wt. % to about 30 wt. % of the formulation and a polymercomprises at least 70% of the formulation. In some embodiments, thepolymer in this formulation is polyorthoester.

In some embodiments, the formulation comprises a drug depot thatcomprises a biodegradable polyorthoester. The mechanism of thedegradation process of the polyorthoester can be hydrolytical orenzymatical in nature, or both. In various embodiments, the degradationcan occur either at the surface of the drug depot (heterogeneous orsurface erosion) or uniformly throughout the drug delivery system depot(homogeneous or bulk erosion). Polyorthoester can be obtained from A.P.Pharma, Inc. (Redwood City, Calif.) or through the reaction of abis(ketene acetal) such as3,9-diethylidene-2,4,8,10-tetraoxospiro[5,5]undecane (DETOSU) withsuitable combinations of diol(s) and/or polyol(s) such as1,4-trans-cyclohexanedimethanol and 1,6-hexanediol or by any otherchemical reaction that produces a polymer comprising orthoestermoieties.

In some embodiments, there is a pharmaceutical formulation in a drugdepot comprising: clonidine, wherein the clonidine is in the form of ahydrochloride salt, and comprises from about 0.1 wt % to about 30 wt %of the formulation or about 1 wt. % to about 20 wt. % of theformulation, and at least one biodegradable polymer, wherein the atleast one biodegradable polymer comprises poly(lactide-co-glycolide) (orpoly(lactic-co-glycolic acid)) or poly(orthoester) or a combinationthereof, and said at least one biodegradable polymer comprises at least70 wt % or 80 wt. % of said formulation.

In some embodiments, there is a pharmaceutical formulation comprisingclonidine, wherein the clonidine is in a mixture of clonidinehydrochloride and clonidine base and the mixture comprises from about0.1 wt. % to about 30 wt. % of the formulation and a polymer comprisesat least 70% of the formulation. In some embodiments, the polymer inthis formulation is polyorthoester.

In some embodiments, there are methods for treating pain. These methodscomprise: administering a pharmaceutical composition to an organism,wherein said pharmaceutical composition comprises from about 1 wt. % toabout 20 wt. % of the formulation, and at least one biodegradablepolymer. In some embodiments, the loading is from about 5 wt. % to about10 wt. %. In some embodiments, the loading is from about 10 wt. % toabout 20 wt. %.

In some embodiment there is a higher loading of clonidine, e.g., atleast 20 wt. %, at least 30 wt. %, at least 40 wt. %, at least 50 wt. %,at least 60 wt. %, at least 70 wt. %, at least 80 wt. %, or at least 90wt. %.

In some embodiments, the drug depot contains excipients along with theclonidine. Exemplary excipients that may be formulated with clonidine inaddition to the biodegradable polymer include but are not limited to MgO(e.g., 1 wt. %), 5050 DLG 6E, 5050 DLG 1A, mPEG, TBO-Ac, mPEG, Span-65,Span-85, pluronic F127, TBO-Ac, sorbital, cyclodextrin, maltodextrin,pluronic F68, CaCl, 5050 DLG-7A and combinations thereof. In someembodiments, the excipients comprise from about 0.001 wt. % to about 50wt. % of the formulation. In some embodiments, the excipients comprisefrom about 0.001 wt. % to about 40 wt. % of the formulation. In someembodiments, the excipients comprise from about 0.001 wt. % to about 30wt. % of the formulation. In some embodiments, the excipients comprisefrom about 0.001 wt. % to about 20 wt. % of the formulation. In someembodiments, the excipients comprise from about 0.001 wt. % to about 10wt. % of the formulation. In some embodiments, the excipients comprisefrom about 0.001 wt. % to about 50 wt. % of the formulation. In someembodiments, the excipients comprise from about 0.001 wt. % to about 2wt. % of the formulation.

A strategy of triangulation may be effective when administering the drugdepot. Thus, a plurality (at least two, at least three, at least four,at least five, at least six, at least seven, etc.) drug depotscomprising the pharmaceutical formulations (e.g., alpha adrenergicreceptor agonist) may be placed around the target tissue site (alsoknown as the pain generator or pain generation site, such as forexample, herniated disc) such that the target tissue site falls within aregion that is either between the formulations when there are two, orwithin an area whose perimeter is defined by a set of plurality offormulations.

In some embodiments, the formulations are slightly rigid with varyinglength, widths, diameters, etc. For example, certain formulations mayhave a diameter of 0.50 mm and a length of 4 mm. It should be noted thatparticle size may be altered by techniques such as using a mortar andpestle, jet-drying or jet milling.

In some embodiments, clonidine is released at a rate of 2-3 μg per dayfor a period of at least three days. In some embodiments, this releaserate continues for, at least ten days, at least fifteen days, at leasttwenty-five days, at least fifty days, at least ninety days, at leastone hundred days, at least one-hundred and thirty-five days, at leastone-hundred and fifty days, or at least one hundred and eighty days. Forsome embodiments, 300-425 micrograms of clonidine as formulated with abiopolymer are implanted into a person at or near a target tissue site.If clonidine is implanted at multiple sites that triangulate the targetsite then in some embodiments, the total amount of clonidine at eachsite is a fraction of the total 300-425 micrograms. For example, one mayimplant a single dose of 324 micrograms at one site, or two separatedoses of 162 micrograms at two sites, or three separate dose of 108micrograms at three sites that triangulate the tissue site. It isimportant to limit the total dosage to an amount less than that whichwould be harmful to the organism. However, in some embodiments, althoughwhen there are a plurality of sites each site may contain less than thetotal dose that might have been administered in a single application, itis important to remember that each site will independently have arelease profile, and the biopolymers' concentration and substance shouldbe adjusted accordingly to ensure that the sustain release occurs oversufficient time.

In some embodiments, there is a drug depot comprising clonidine orclonidine hydrochloride and a polymer, wherein the polymer is one moreof various embodiments, the drug depot comprisespoly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone or a combination thereof.

In one exemplary dosing regimen, a rat may be provided with sufficientclonidine in a biodegradable polymer to provide sustain release of 0.240μg/day for 135 days. The total amount of clonidine that is administeredover this time period would be approximately 32.4 μg. In anotherexemplary dosing regimen, a human is provided with sufficient clonidinein a biodegradable polymer to provide sustain release of 2.4 μg/day for135 days. The total amount of clonidine that is administered over thistime period would be approximately 324 μg.

When using a plurality of pellets, the pellet number is based on theamount of drug loading into a pellet of appropriate size (i.e., 0.5 mmdiameter×4 mm length) and how much drug is needed (e.g., approximately325 μg clonidine (3 pellets)). In some embodiments there is a polymerthat releases a bolus amount of compound over the first few (˜5) daysbefore it settles down and releases 2.5 mg/day for 135 days. Anexemplary formulation is 5% wt. clonidine, 100 DL 5E.

In some embodiments, the polymer depots of present application enableone to provide efficacy of the active ingredient that is equivalent tosubcutaneous injections that deliver more than 2.5 times as much drug.

Fluocinolone

In one embodiment, in addition to the alpha agonist, theanti-inflammatory agent in the depot comprises fluocinolone or apharmaceutically acceptable salt thereof such as the acetonide salt.Fluocinolone is available from various pharmaceutical manufacturers. Thedosage of fluocinolone may be from approximately 0.0005 to approximately100 μg/day. Additional dosages of fluocinolone include fromapproximately 0.0005 to approximately 50 μg/day; approximately 0.0005 toapproximately 25 μg/day; approximately 0.0005 to approximately 10μg/day; approximately 0.0005 to approximately 5 μg/day; approximately0.0005 to approximately 1 μg/day; approximately 0.0005 to approximately0.75 μg/day; approximately 0.0005 to approximately 0.5 μg/day;approximately 0.0005 to approximately 0.25 μg/day; approximately 0.0005to approximately 0.1 μg/day; approximately 0.0005 to approximately 0.075μg/day; approximately 0.0005 to approximately 0.05 μg/day; approximately0.001 to approximately 0.025 μg/day; approximately 0.001 toapproximately 0.01 μg/day; approximately 0.001 to approximately 0.0075μg/day; approximately 0.001 to approximately 0.005 μg/day; approximately0.001 to approximately 0.025 μg/day; and approximately 0.002 μg/day. Inanother embodiment, the dosage of fluocinolone is from approximately0.001 to approximately 15 μg/day. In another embodiment, the dosage offluocinolone is from approximately 0.001 to approximately 10 μg/day. Inanother embodiment, the dosage of fluocinolone is from approximately0.001 to approximately 5 μg/day. In another embodiment, the dosage offluocinolone is from approximately 0.001 to 2.5 μg/day. In someembodiments, the amount of fluocinolone is between 40 and 600 μg/day. Insome embodiments, the amount of fluocinolone is between 200 and 400μg/day.

Dexamethasone

In one embodiment of the present invention, in addition to the alphaagonist, the anti-inflammatory agent in the drug depot is dexamethasonefree base or dexamethasone acetate, also referred to as8S,9R,10S,11S,13S,14S,16R,17R)-9-Fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,11,12,14,15,16octahydrocyclopenta[a]-phenanthren-3-one), or a pharmaceuticallyacceptable salt thereof, which is available from various manufacturers.

In various embodiments, dexamethasone may be released from the depot ata dose of about 10 pg to about 80 mg/day, about 2.4 ng/day to about 50mg/day, about 50 ng/day to about 2.5 mg/day, about 250 ng/day to about250 ug/day, about 250 ng/day to about 50 ug/day, about 250 ng/day toabout 25 ug/day, about 250 ng/day to about 1 ug/day, about 300 ng/day toabout 750 ng/day or about 0.50 ug/day. In various embodiments, the dosemay be about 0.01 to about 10 μg/day or about 1 ng to about 120 μg/day.

In one exemplary embodiment, the dexamethasone is dexamethasone sodiumphosphate.

GED

In one embodiment, in addition to the alpha agonist, the therapeuticagent in the drug depot is GED (guanidinoethyldisulfide), which is aninducible nitric oxide synthase inhibitor having anti-inflammatoryproperties. GED may be in its hydrogen carbonate salt form.

The dosage of GED may be from approximately 0.0005 μg/day toapproximately 100 mg/day. Additional dosages of GED include fromapproximately 0.0005 μg/day to approximately 50 mg/day; approximately0.0005 μg/day to approximately 10 mg/day; approximately 0.0005 μg/day toapproximately 1 mg/day; approximately 0.0005 to approximately 800μg/day; approximately 0.0005 to approximately 50 μg/day; approximately0.001 to approximately 45 μg/day; approximately 0.001 to approximately40 μg/day; approximately 0.001 to approximately 35 μg/day; approximately0.0025 to approximately 30 g/day; approximately 0.0025 to approximately25 μg/day; approximately 0.0025 to approximately 20 μg/day; andapproximately 0.0025 to approximately 15 μg/day. In another embodiment,the dosage of GED is from approximately 0.005 to approximately 15μg/day. In another embodiment, the dosage of GED is from approximately0.005 to approximately 10 ηg/day. In another embodiment, the dosage ofGED is from approximately 0.005 to approximately 5 μg/day. In anotherembodiment, the dosage of GED is from approximately 0.005 to 2.5 μg/day.In some embodiments, the amount of GED is between 40 and 600 μg/day. Insome embodiments, the amount of GED is between 200 and 400 μg/day.

In one exemplary embodiment the dosage of GED is between 0.5 and 4mg/day. In another exemplary embodiment the dosage of GED is between0.75 and 3.5 mg/day.

Lovastatin

In one exemplary embodiment, in addition to the alpha-agonist, theanti-inflammatory agent in the drug depot comprises lovastatin.Lovastatin is a statin that may be obtained from various manufacturersin various forms (e.g., injection, powder, etc.). For example,lovastatin may be obtained from Merck as Mevacor® (see U.S. Pat. No.4,231,938, the entire disclosure is herein incorporated by reference).Suitable pharmaceutically acceptable salts of lovastatin include one ormore compounds derived from bases such as sodium hydroxide, potassiumhydroxide, lithium hydroxide, calcium hydroxide,1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide,aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide ororganic amines such as N-methylglucamine, choline, arginine or the likeor combinations thereof. Suitable pharmaceutically acceptable salts oflovastatin include lithium, calcium, hemicalcium, sodium, potassium,magnesium, aluminum, ferrous or ferric salts thereof or a combinationthereof.

In various embodiments, the therapeutically effective amount oflovastatin comprises from about 0.1 pg to about 2000 mg, for example,0.1 ng to 1000 mg, 500 mg, 100 mg, 50 mg, 25 mg, 10 mg, 1 mg, 50 μg, 25μg, 10 μg, 1 μg, 500 ng, 250 ng, 100 ng, 75 ng, 50 ng, 25 ng, 15 ng, 10ng, 5 ng, or 1 ng of lovastatin per day. In various embodiments, thedosage may be, for example from about 3 ng/day to 0.3 μg/day.

Morphine

In one embodiment of the present invention, in addition to the alphaagonist, the analgesic agent in the drug depot is morphine. Morphine isalso referred to as(5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol and has thechemical formula C₁₇H₁₉NO₃. Morphine and a pharmaceutically acceptablesalt thereof is available from various manufacturers. In one exemplaryembodiment, the morphine comprises morphine sulfate or hydrochloride.

The dosage of the morphine may be from 0.1 mg to 1000 mg per day. Forexample, the dosage of morphine may be for example, 0.1 mg to 2 mg, 5mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200mg of morphine per day.

Tramadol

In one embodiment, in addition to the alpha agonist, the analgesic agentin the drug depot is tramadol. Tramadol is also referred to as(±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanolhydrochloride and has the chemical formula C₁₆H₂₅NO₂. Tramadol or apharmaceutically acceptable salt thereof is available from variousmanufacturers. In various embodiments, tramadol HCL was used.

The dosage of the tramadol may be from 0.01 mg to 500 mg per day. Forexample, the dosage of tramadol may be for example, 0.1 mg to 2 mg, 5mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55mg, 60 mg, 65 mg, 70 mg, 75 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200mg, or 500 mg of tramadol per day.

In one embodiment, the drug depot contains sufficient tramadol torelease between 2.5 and 30 mg/kg/day. In another embodiment the drugdepot contains sufficient tramadol to release between 3 and 27.5mg/kg/day.

The alpha adrenergic agonist may also be administered with non-activeingredients. These non-active ingredients may have multi-functionalpurposes including the carrying, stabilizing and controlling the releaseof the therapeutic agent(s). The sustained release process, for example,may be by a solution-diffusion mechanism or it may be governed by anerosion-sustained process. Typically, the depot will be a solid orsemi-solid formulation comprised of a biocompatible material that can bebiodegradable. The term “solid” is intended to mean a rigid material,while “semi-solid” is intended to mean a material that has some degreeof flexibility, thereby allowing the depot to bend and conform to thesurrounding tissue requirements.

In various embodiments, the non-active ingredients will be durablewithin the tissue site for a period of time equal to or greater than(for biodegradable components) or greater than (for non-biodegradablecomponents) the planned period of drug delivery.

In some embodiments, the depot material may have a melting point orglass transition temperature close to or higher than body temperature,but lower than the decomposition or degradation temperature of thetherapeutic agent. However, the pre-determined erosion of the depotmaterial can also be used to provide for slow release of the loadedtherapeutic agent(s).

In various embodiments, the drug depot may not be fully biodegradable.For example, the drug depot may comprise polyurethane, polyurea,polyether(amide), PEBA, thermoplastic elastomeric olefin, copolyester,and styrenic thermoplastic elastomer, steel, aluminum, stainless steel,titanium, metal alloys with high non-ferrous metal content and a lowrelative proportion of iron, carbon fiber, glass fiber, plastics,ceramics or combinations thereof. Typically, these types of drug depotsmay need to be removed.

In some instance, it may be desirable to avoid having to remove the drugdepot after use. In those instances, the depot may comprise abiodegradable material. There are numerous materials available for thispurpose and having the characteristic of being able to breakdown ordisintegrate over a prolonged period of time when positioned at or nearthe target tissue. As a function of the chemistry of the biodegradablematerial, the mechanism of the degradation process can be hydrolyticalor enzymatical in nature, or both. In various embodiments, thedegradation can occur either at the surface (heterogeneous or surfaceerosion) or uniformly throughout the drug delivery system depot(homogeneous or bulk erosion).

In various embodiments, the depot may comprise a bioabsorbable, and/or abiodegradable biopolymer that may provide immediate release, orsustained release of the at least one analgesic agent and/or at leastone anti-inflammatory agent. Examples of suitable sustained releasebiopolymers include but are not limited to poly(alpha-hydroxy acids),poly(lactide-co-glycolide) (PLGA or PLG), polylactide (PLA),polyglycolide (PG), polyethylene glycol (PEG) conjugates ofpoly(alpha-hydroxy acids), polyorthoesters, polyaspirins,polyphosphagenes, collagen, starch, pre-gelatinized starch, hyaluronicacid, chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs,such as alpha tocopheryl acetate, d-alpha tocopheryl succinate,D,L-lactide, or L-lactide, -caprolactone, dextrans, vinylpyrrolidone,polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive),methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics),PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407,PEG-PLGA-PEG triblock copolymers, SAIB (sucrose acetate isobutyrate) orcombinations thereof. As persons of ordinary skill are aware, mPEG maybe used as a plasticizer for PLGA, but other polymers/excipients may beused to achieve the same effect. mPEG imparts malleability to theresulting formulations. In some embodiments, these biopolymers may alsobe coated on the drug depot to provide the desired release profile. Insome embodiments, the coating thickness may be thin, for example, fromabout 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 microns to thickercoatings 60, 65, 70, 75, 80, 85, 90, 95, or 100 microns to delay releaseof the drug from the depot. In some embodiments, the range of thecoating on the drug depot ranges from about 5 microns to about 250microns or 5 microns to about 200 microns to delay release from the drugdepot.

Where different combinations of polymers are used (bi, tri (e.g.,PLGA-PEO-PLGA) or terpolymers), they may be used in different molarratios, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1. In variousembodiments, for the 130 day release, the depot comprises 50:50 PLGA to100 PLA. The molecular weight range is 0.45 to 0.8 dI/g.

In various embodiments, the molecular weight of the polymer can be awide range of values. The average molecular weight of the polymer can befrom about 1000 to about 10,000,000; or about 1,000 to about 1,000,000;or about 5,000 to about 500,000; or about 10,000 to about 100,000; orabout 20,000 to 50,000.

In some embodiments, the at least one biodegradable polymer comprisespoly(lactic-co-glycolic acid) (PLGA) or poly(orthoester) (POE) or acombination thereof. The poly(lactic-co-glycolic acid) may comprise amixture of polyglycolide (PGA) and polylactide and in some embodiments,in the mixture, there is more polylactide than polyglycolide. In variousother embodiments there is 100% polylactide and 0% polyglycolide; 95%polylactide and 5% polyglycolide; 90% polylactide and 10% polyglycolide;85% polylactide and 15% polyglycolide; 80% polylactide and 20%polyglycolide; 75% polylactide and 25% polyglycolide; 70% polylactideand 30% polyglycolide; 65% polylactide and 35% polyglycolide; 60%polylactide and 40% polyglycolide; 55% polylactide and 45%polyglycolide; 50% polylactide and 50% polyglycolide; 45% polylactideand 55% polyglycolide; 40% polylactide and 60% polyglycolide; 35%polylactide and 65% polyglycolide; 30% polylactide and 70%polyglycolide; 25% polylactide and 75% polyglycolide; 20% polylactideand 80% polyglycolide; 15% polylactide and 85% polyglycolide; 10%polylactide and 90% polyglycolide; 5% polylactide and 95% polyglycolide;and 0% polylactide and 100% polyglycolide.

In various embodiments that comprise both polylactide and polyglycolide;there is at least 95% polylactide; at least 90% polylactide; at least85% polylactide; at least 80% polylactide; at least 75% polylactide; atleast 70% polylactide; at least 65% polylactide; at least 60%polylactide; at least 55%; at least 50% polylactide; at least 45%polylactide; at least 40% polylactide; at least 35% polylactide; atleast 30% polylactide; at least 25% polylactide; at least 20%polylactide; at least 15% polylactide; at least 10% polylactide; or atleast 5% polylactide; and the remainder of the biopolymer beingpolyglycolide.

In various embodiments, the drug depot comprisespoly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide(PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-ε-caprolactone,D,L-lactide-co-glycolide-co-ε-caprolactone, glycolide-caprolactone or acombination thereof.

As persons of ordinary skill in the art are aware, implantableelastomeric depot compositions having a blend of polymers with differentend groups are used the resulting formulation will have a lower burstindex and a regulated duration of delivery. For example, one may usepolymers with acid (e.g., carboxylic acid) and ester end groups (e.g.,lauryl, methyl or ethyl ester end groups).

Additionally, by varying the comonomer ratio of the various monomersthat form a polymer (e.g., the UG/CL or G/CL ratio for a given polymer)there will be a resulting depot composition having a regulated burstindex and duration of delivery. For example, a depot composition havinga polymer with a UG ratio of 50:50 may have a short duration of deliveryranging from about two days to about one month; a depot compositionhaving a polymer with a L/G ratio of 65:35 may have a duration ofdelivery of about two months; a depot composition having a polymer witha UG ratio of 75:25 or L/CL ratio of 75:25 may have a duration ofdelivery of about three months to about four months; a depot compositionhaving a polymer ratio with a L/G ratio of 85:15 may have a duration ofdelivery of about five months; a depot composition having a polymer witha L/CL ratio of 25:75 or PLA may have a duration of delivery greaterthan or equal to six months; a depot composition having a terpolymer ofCL/G/L (CL refers to caprolactone, G refers to glycolic acid and Lrefers to lactic acid) with G greater than 50% and L greater than 10%may have a duration of delivery of about one month and a depotcomposition having a terpolymer of CL/G/L with G less than 50% and Lless than 10% may have a duration months up to six months. In general,increasing the G content relative to the CL content shortens theduration of delivery whereas increasing the CL content relative to the Gcontent lengthens the duration of delivery.

In some embodiments, the biodegradable polymer comprises at least 10 wt%, at least 50 wt. %, at least 60 wt. %, at least 70 wt. %, at least 80wt. %, at least 85 wt. %, at least 90 wt. %, at least 95 wt. %, or atleast 99 wt. % of the formulation. In some embodiments, the at least onebiodegradable polymer and the at least one alpha agonist are the onlycomponents of the pharmaceutical formulation.

In some embodiments, at least 75% of the particles of the drug depothave a size from about 1 micrometer to about 200 micrometers. In someembodiments, at least 85% of the particles have a size from about 1micrometer to about 100 micrometers. In some embodiments, at least 95%of the particles have a size from about 5 micrometer to about 50micrometers. In some embodiments, all of the particles have a size fromabout 10 micrometer to about 50 micrometers.

In some embodiments, at least 75% of the particles of the drug depothave a size from about 5 micrometer to about 20 micrometers. In someembodiments, at least 85% of the particles have a size from about 5micrometers to about 20 micrometers. In some embodiments, at least 95%of the particles have a size from about 5 micrometer to about 20micrometers. In some embodiments, all of the particles have a size fromabout 5 micrometer to about 20 micrometers.

The depot may optionally contain inactive materials such as bufferingagents and pH adjusting agents such as potassium bicarbonate, potassiumcarbonate, potassium hydroxide, sodium acetate, sodium borate, sodiumbicarbonate, sodium carbonate, sodium hydroxide or sodium phosphate;degradation/release modifiers; drug release adjusting agents;emulsifiers; preservatives such as benzalkonium chloride, chlorobutanol,phenylmercuric acetate and phenylmercuric nitrate, sodium bisulfite,sodium bisulfate, sodium thiosulfate, thimerosal, methylparaben,polyvinyl alcohol and phenylethyl alcohol; solubility adjusting agents;stabilizers; and/or cohesion modifiers. Typically, any such inactivematerials will be present within the range of 0-75 wt %, and moretypically within the range of 0-30 wt %. If the depot is to be placed inthe spinal area, in various embodiments, the depot may comprise sterilepreservative free material.

The depot can be different sizes, shapes and configurations. There areseveral factors that can be taken into consideration in determining thesize, shape and configuration of the drug depot. For example, both thesize and shape may allow for ease in positioning the drug depot at thetarget tissue site that is selected as the implantation or injectionsite. In addition, the shape and size of the system should be selectedso as to minimize or prevent the drug depot from moving afterimplantation or injection. In various embodiments, the drug depot can beshaped like a pellet, a sphere, a cylinder such as a rod or fiber, aflat surface such as a disc, film or sheet or the like. Flexibility maybe a consideration so as to facilitate placement of the drug depot. Invarious embodiments, the drug depot can be different sizes, for example,the drug depot may be a length of from about 0.5 mm to 5 mm and have adiameter of from about 0.01 to about 4 mm. In various embodiments, thedrug depot may have a layer thickness of from about 0.005 to 1.0 mm,such as, for example, from 0.05 to 0.75 mm.

In various embodiments, when the drug depot comprises a pellet, it maybe placed at the incision site before the site is closed. The pellet mayfor example be made of thermoplastic materials. Additionally, specificmaterials that may be advantageous for use in the pellet include but arenot limited to the compounds identified above as sustained releasebiopolymers. The drug depot may be formed by mixing the at least onealpha adrenergic agonist with the polymer.

Radiographic markers can be included on the drug depot to permit theuser to position the depot accurately into the target site of thepatient. These radiographic markers will also permit the user to trackmovement and degradation of the depot at the site over time. In thisembodiment, the user may accurately position the depot in the site usingany of the numerous diagnostic imaging procedures. Such diagnosticimaging procedures include, for example, X-ray imaging or fluoroscopy.Examples of such radiographic markers include, but are not limited to,barium, bismuth, tantalum, tungsten, iodine, calcium phosphate, and/ormetal beads or particles. In various embodiments, the radiographicmarker could be a spherical shape or a ring around the depot.

In various embodiments, the gel has a pre-dosed viscosity in the rangeof about 1 to about 2000 centipoise (cps), 1 to about 500 cps, or 1 toabout 200 cps or 100 cps. After the gel is administered to the targetsite, the viscosity of the gel will increase and the gel will have amodulus of elasticity (Young's modulus) in the range of about 1×−10⁻² toabout 6×10⁵ dynes/cm², or 2×10⁴ to about 5×10⁵ dynes/cm², or 5×10⁴ toabout 5×10⁵ dynes/cm².

In one embodiment, a depot is provided that contains an adherent gelcomprising at least one alpha adrenergic agonist that is evenlydistributed throughout the gel. The gel may be of any suitable type, aspreviously indicated, and should be sufficiently viscous so as toprevent the gel from migrating from the targeted delivery site oncedeployed; the gel should, in effect, “stick” or adhere to the targetedtissue site. The gel may, for example, solidify upon contact with thetargeted tissue or after deployment from a targeted delivery system. Thetargeted delivery system may be, for example, a syringe, a catheter,needle or cannula or any other suitable device. The targeted deliverysystem may inject the gel into or on the targeted tissue site. Thetherapeutic agent may be mixed into the gel prior to the gel beingdeployed at the targeted tissue site. In various embodiments, the gelmay be part of a two-component delivery system and when the twocomponents are mixed, a chemical process is activated to form the geland cause it to stick or to adhere to the target tissue.

In various embodiments, a gel is provided that hardens or stiffens afterdelivery. Typically, hardening gel formulations may have a pre-dosedmodulus of elasticity in the range of about 1×−10⁻² to about 3×10⁵dynes/cm², or 2×10⁴ to about 2×10⁵ dynes/cm², or 5×10⁴ to about 1×10⁵dynes/cm². The post-dosed hardening gels (after delivery) may have arubbery consistency and have a modulus of elasticity in the range ofabout 1×10⁴ to about 2×10⁶ dynes/cm², or 1×10⁵ to about 7×10⁵ dynes/cm²,or 2×10⁵ to about 5×10⁵ dynes/cm².

In various embodiments, for those gel formulations that contain apolymer, the polymer concentration may affect the rate at which the gelhardens (e.g., a gel with a higher concentration of polymer maycoagulate more quickly than gels having a lower concentration ofpolymer). In various embodiments, when the gel hardens, the resultingmatrix is solid but is also able to conform to the irregular surface ofthe tissue (e.g., recesses and/or projections in bone).

The percentage of polymer present in the gel may also affect theviscosity of the polymeric composition. For example, a compositionhaving a higher percentage by weight of polymer is typically thicker andmore viscous than a composition having a lower percentage by weight ofpolymer. A more viscous composition tends to flow more slowly.Therefore, a composition having a lower viscosity may be preferred insome instances.

In various embodiments, the molecular weight of the gel can be varied byany one of the many methods known in the art. The choice of method tovary molecular weight is typically determined by the composition of thegel (e.g., polymer versus non-polymer). For example in variousembodiments, when the gel comprises one or more polymers, the degree ofpolymerization can be controlled by varying the amount of polymerinitiators (e.g. benzoyl peroxide), organic solvents or activator (e.g.DMPT), crosslinking agents, polymerization agent, incorporation of chaintransfer or chain capping agents and/or reaction time.

Suitable gel polymers may be soluble in an organic solvent. Thesolubility of a polymer in a solvent varies depending on thecrystallinity, hydrophobicity, hydrogen-bonding and molecular weight ofthe polymer. Lower molecular weight polymers will normally dissolve morereadily in an organic solvent than high-molecular weight polymers. Apolymeric gel, which includes a high molecular weight polymer, tends tocoagulate or solidify more quickly than a polymeric composition, whichincludes a low-molecular weight polymer. Polymeric gel formulations,which include high molecular weight polymers, also tend to have a highersolution viscosity than a polymeric gel, which include a low-molecularweight polymer.

When the gel is designed to be a flowable gel, it can vary from lowviscosity, similar to that of water, to a high viscosity, similar tothat of a paste, depending on the molecular weight and concentration ofthe polymer used in the gel. The viscosity of the gel can be varied suchthat the polymeric composition can be applied to a patient's tissues byany convenient technique, for example, by brushing, spraying, dripping,injecting, or painting. Different viscosities of the gel will depend onthe technique used to apply the composition.

In various embodiments, the gel has an inherent viscosity (abbreviatedas “I.V.” and units are in deciliters/gram), which is a measure of thegel's molecular weight and degradation time (e.g., a gel with a highinherent viscosity has a higher molecular weight and may have a longerdegradation time). Typically, a gel with a high molecular weightprovides a stronger matrix and the matrix takes more time to degrade. Incontrast, a gel with a low molecular weight degrades more quickly andprovides a softer matrix. In various embodiments, the gel has amolecular weight, as shown by the inherent viscosity, from about 0.10dL/g to about 1.2 dL/g or from about 0.10 dL/g to about 0.40 dL/g.

In various embodiments, the gel can have a viscosity of about 300 toabout 5,000 centipoise (cp). In other embodiments, the gel can have aviscosity of from about 5 to about 300 cps, from about 10 cps to about50 cps, from about 15 cps to about 75 cps at room temperature. The gelmay optionally have a viscosity enhancing agent such as, for example,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose and salts thereof, Carbopol,poly-(hydroxyethylmethacrylate), poly-(methoxyethylmethacrylate),poly(methoxyethoxyethyl methacrylate), polymethylmethacrylate (PMMA),methylmethacrylate (MMA), gelatin, polyvinyl alcohols, propylene glycol,PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900,PEG 1000, PEG 1450, PEG 3350, PEG 4500, PEG 8000 or combinationsthereof.

In various embodiments, when a polymer is employed in the gel, thepolymeric composition includes about 10 wt % to about 90 wt % or about30 wt % to about 60 wt % of the polymer.

In various embodiments, the gel is a hydrogel made of high molecularweight biocompatible elastomeric polymers of synthetic or naturalorigin. A desirable property for the hydrogel to have is the ability torespond rapidly to mechanical stresses, particularly shears and loads,in the human body.

Hydrogels obtained from natural sources are particularly appealingbecause they are more likely to be biodegradable and biocompatible forin vivo applications. Suitable hydrogels include natural hydrogels, suchas, for example, gelatin, collagen, silk, elastin, fibrin andpolysaccharide-derived polymers like agarose, and chitosan, glucomannangel, hyaluronic acid, polysaccharides, such as cross-linkedcarboxyl-containing polysaccharides, or a combination thereof. Synthetichydrogels include, but are not limited to those formed from polyvinylalcohol, acrylamides such as polyacrylic acid andpoly(acrylonitrile-acrylic acid), polyurethanes, polyethylene glycol(e.g., PEG 3350, PEG 4500, PEG 8000), silicone, polyolefins such aspolyisobutylene and polyisoprene, copolymers of silicone andpolyurethane, neoprene, nitrile, vulcanized rubber,poly(N-vinyl-2-pyrrolidone), acrylates such as poly(2-hydroxy ethylmethacrylate) and copolymers of acrylates with N-vinyl pyrolidone,N-vinyl lactams, polyacrylonitrile or combinations thereof. The hydrogelmaterials may further be cross-linked to provide further strength asneeded. Examples of different types of polyurethanes includethermoplastic or thermoset polyurethanes, aliphatic or aromaticpolyurethanes, polyetherurethane, polycarbonate-urethane or siliconepolyether-urethane, or a combination thereof.

In various embodiments, rather than directly admixing the therapeuticagents into the gel, microspheres may be dispersed within the gel, themicrospheres being loaded with at least one analgesic agent and/or atleast one anti-inflammatory agent. In one embodiment, the microspheresprovide for a sustained release of the at least one alpha-2 adrenergicagonist. In yet another embodiment, the gel, which is biodegradable,prevents the microspheres from releasing the at least one alphaadrenergic agonist; the microspheres thus do not release the at leastone alpha adrenergic agonist until it has been released from the gel.For example, a gel may be deployed around a target tissue site (e.g., anerve root). Dispersed within the gel are a plurality of microspheresthat encapsulate the desired therapeutic agent. Certain of thesemicrospheres degrade once released from the gel, thus releasing the atleast one alpha adrenergic agonist. The alpha adrenergic agonist may beplaced into separate microspheres and then the microspheres combined, orthe active ingredients can first be combined and then placed into themicrospheres together.

Microspheres, much like a fluid, may disperse relatively quickly,depending upon the surrounding tissue type, and hence disperse the atleast one analgesic agent and at least one anti-inflammatory agent. Insome embodiments, the diameter of the microspheres range from about 10microns in diameter to about 200 microns in diameter. In someembodiments they range from about 20 to 120 microns in diameters.Methods for making microspheres include but are not limited to solventevaporation, phase separation and fluidized bed coating. In somesituations, this may be desirable; in others, it may be more desirableto keep the at least one alpha adrenergic receptor agonist tightlyconstrained to a well-defined target site.

The present invention also contemplates the use of adherent gels to soconstrain dispersal of the therapeutic agent. These gels may bedeployed, for example, in a disc space, in a spinal canal, or insurrounding tissue.

Cannulas and Needles

It will be appreciated by those with skill in the art that the depot canbe administered to the target site using a “cannula” or “needle” thatcan be a part of a drug delivery device e.g., a syringe, a gun drugdelivery device, or any medical device suitable for the application of adrug to a targeted organ or anatomic region. The cannula or needle ofthe drug depot device is designed to cause minimal physical andpsychological trauma to the patient.

Cannulas or needles include tubes that may be made from materials, suchas for example, polyurethane, polyurea, polyether(amide), PEBA,thermoplastic elastomeric olefin, copolyester, and styrenicthermoplastic elastomer, steel, aluminum, stainless steel, titanium,metal alloys with high non-ferrous metal content and a low relativeproportion of iron, carbon fiber, glass fiber, plastics, ceramics orcombinations thereof. The cannula or needle may optionally include oneor more tapered regions. In various embodiments, the cannula or needlemay be beveled. The cannula or needle may also have a tip style vitalfor accurate treatment of the patient depending on the site forimplantation. Examples of tip styles include, for example, Trephine,Coumand, Veress, Huber, Seldinger, Chiba, Francine, Bias, Crawford,deflected tips, Hustead, Lancet, or Tuohey. In various embodiments, thecannula or needle may also be non-coring and have a sheath covering itto avoid unwanted needle sticks.

The dimensions of the hollow cannula or needle, among other things, willdepend on the site for implantation. For example, the width of theepidural space is only about 3-5 mm for the thoracic region and about5-7 mm for the lumbar region. Thus, the needle or cannula, in variousembodiments, can be designed for these specific areas. In variousembodiments, the cannula or needle may be inserted using atransforaminal approach in the spinal foramen space, for example, alongan inflammed nerve root and the drug depot implanted at this site fortreating the condition. Typically, the transforaminal approach involvesapproaching the intervertebral space through the intervertebralforamina.

Some examples of lengths of the cannula or needle may include, but arenot limited to, from about 50 to 150 mm in length, for example, about 65mm for epidural pediatric use, about 85 mm for a standard adult andabout 10 mm for an obese adult patient. The thickness of the cannula orneedle will also depend on the site of implantation. In variousembodiments, the thickness includes, but is not limited to, from about0.05 to about 1.655. The gauge of the cannula or needle may be thewidest or smallest diameter or a diameter in between for insertion intoa human or animal body. The widest diameter is typically about 14 gauge,while the smallest diameter is about 25 gauge. In various embodimentsthe gauge of the needle or cannula is about 18 to about 22 gauge.

In various embodiments, like the drug depot and/or gel, the cannula orneedle includes dose radiographic markers that indicate location at ornear the site beneath the skin, so that the user may accurately positionthe depot at or near the site using any of the numerous diagnosticimaging procedures. Such diagnostic imaging procedures include, forexample, X-ray imaging or fluoroscopy. Examples of such radiographicmarkers include, but are not limited to, barium, calcium phosphate,and/or metal beads or particles.

In various embodiments, the needle or cannula may include a transparentor translucent portion that can be visualizable by ultrasound,fluoroscopy, x-ray, or other imaging techniques. In such embodiments,the transparent or translucent portion may include a radiopaque materialor ultrasound responsive topography that increases the contrast of theneedle or cannula relative to the absence of the material or topography.

Sterilization

The drug depot, and/or medical device to administer the drug may besterilizable. In various embodiments, one or more components of the drugdepot, and/or medical device to administer the drug are sterilized byradiation in a terminal sterilization step in the final packaging.Terminal sterilization of a product provides greater assurance ofsterility than from processes such as an aseptic process, which requireindividual product components to be sterilized separately and the finalpackage assembled in a sterile environment.

Typically, in various embodiments, gamma radiation is used in theterminal sterilization step, which involves utilizing ionizing energyfrom gamma rays that penetrates deeply in the device. Gamma rays arehighly effective in killing microorganisms, they leave no residues norhave sufficient energy to impart radioactivity to the device. Gamma rayscan be employed when the device is in the package and gammasterilization does not require high pressures or vacuum conditions,thus, package seals and other components are not stressed. In addition,gamma radiation eliminates the need for permeable packaging materials.

In various embodiments, electron beam (e-beam) radiation may be used tosterilize one or more components of the device. E-beam radiationcomprises a form of ionizing energy, which is generally characterized bylow penetration and high-dose rates. E-beam irradiation is similar togamma processing in that it alters various chemical and molecular bondson contact, including the reproductive cells of microorganisms. Beamsproduced for e-beam sterilization are concentrated, highly-chargedstreams of electrons generated by the acceleration and conversion ofelectricity. E-beam sterilization may be used, for example, when thedrug depot is included in a gel.

Other methods may also be used to sterilize the depot and/or one or morecomponents of the device, including, but not limited to, gassterilization, such as, for example, with ethylene oxide or steamsterilization.

Kits

In various embodiments, a kit is provided that may include additionalparts along with the drug depot and/or medical device combined togetherto be used to implant the drug depot (e.g., pellet). The kit may includethe drug depot device in a first compartment. The second compartment mayinclude a canister holding the drug depot and any other instrumentsneeded for the localized drug delivery. A third compartment may includegloves, drapes, wound dressings and other procedural supplies formaintaining sterility of the implanting process, as well as aninstruction booklet. A fourth compartment may include additionalcannulas and/or needles. A fifth compartment may include the agent forradiographic imaging. Each tool may be separately packaged in a plasticpouch that is radiation sterilized. A cover of the kit may includeillustrations of the implanting procedure and a clear plastic cover maybe placed over the compartments to maintain sterility.

Administration

In various embodiments, the alpha adrenergic agonist may be parenterallyadministered. The term “parenteral” as used herein refers to modes ofadministration, which bypass the gastrointestinal tract, and include forexample, localized intravenous, intramuscular, continuous orintermittent infusion, intraperitoneal, intrasternal, subcutaneous,intra-operatively, intrathecally, intradiscally, peridiscally,epidurally, perispinally, intraarticular injection or combinationsthereof.

Parenteral administration may additionally include, for example, aninfusion pump that locally administers a pharmaceutical composition(e.g., alpha adrenergic agonist) through a catheter near the spine, animplantable mini-pump that can be inserted at or near the target site,an implantable controlled release device or sustained release deliverysystem that can release a certain amount of the composition continuouslyper hour or in intermittent bolus doses. One example of a suitable pumpfor use is the SynchroMed® (Medtronic, Minneapolis, Minn.) pump. Thispump has three sealed chambers. One contains an electronic module andbattery. The second contains a peristaltic pump and drug reservoir. Thethird contains an inert gas, which provides the pressure needed to forcethe pharmaceutical composition into the peristaltic pump. To fill thepump, the pharmaceutical composition is injected through the reservoirfill port to the expandable reservoir. The inert gas creates pressure onthe reservoir, and the pressure forces the pharmaceutical compositionthrough a filter and into the pump chamber. The pharmaceuticalcomposition is then pumped out of the device from the pump chamber andinto the catheter, which will direct it for deposit at the target site.The rate of delivery of pharmaceutical composition is controlled by amicroprocessor. This allows the pump to be used to deliver similar ordifferent amounts of pharmaceutical composition continuously, atspecific times, or at set intervals between deliveries.

Potential drug delivery devices suitable for adaptation for the methodsdescribed herein include but are not limited to those described, forexample, in U.S. Pat. No. 6,551,290 (assigned to Medtronic, the entiredisclosure is herein incorporated by reference), which describes amedical catheter for target specific drug delivery; U.S. Pat. No.6,571,125 (assigned to Medtronic, the entire disclosure is hereinincorporated by reference), which describes an implantable medicaldevice for controllably releasing a biologically active agent; U.S. Pat.No. 6,594,880 (assigned to Medtronic, the entire disclosure is hereinincorporated by reference), which describes an intraparenchymal infusioncatheter system for delivering therapeutic agents to selected sites inan organism; and U.S. Pat. No. 5,752,930 (assigned to Medtronic, theentire disclosure is herein incorporated by reference), which describesan implantable catheter for infusing equal volumes of agents to spacedsites. In various embodiments, pumps may be adapted with apre-programmable implantable apparatus with a feedback regulateddelivery, a micro-reservoir osmotic release system for controlledrelease of chemicals, small, light-weight devices for delivering liquidmedication, implantable microminiature infusion devices, implantableceramic valve pump assemblies, or implantable infusion pumps with acollapsible fluid chamber. Alzet® osmotic pumps (Durect Corporation,Cupertino, Calif.) are also available in a variety of sizes, pumpingrates, and durations suitable for use in the described methods. Invarious embodiments, a method for delivering a therapeutic agent into asurgery site of a patient is provided. For example, the implantableAlzet® osmotic pump delivers the alpha agonist locally to the targettissue site on a continuous basis (e.g., the Alzet® osmotic pump allowsa continuous infusion in microgram/hr delivery of the alpha agonistintrathecally near the sciatic nerve).

The method of the present application comprises inserting a cannula ator near a target tissue site (e.g., herniated disc) and implanting thedrug depot at the target site beneath the skin of the patient andbrushing, dripping, spraying, injecting, or painting the gel in thetarget site to hold or have the drug depot adhere to the target site. Inthis way unwanted migration of the drug depot away from the target siteis reduced or eliminated.

In various embodiments, because the alpha adrenergic agonist is locallyadministered, therapeutically effective doses may be less than dosesadministered by other routes (oral, topical, etc.). For example, thedrug dose delivered from the drug depot may be, for example, 10%, 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 99.9% less than the oraldosage or injectable dose. In turn, systemic side effects, such as forexample, liver transaminase elevations, hepatitis, liver failure,myopathy, constipation, etc. may be reduced or eliminated.

In various embodiments, to administer the gel having the drug depotdispersed therein to the desired site, first the cannula or needle canbe inserted through the skin and soft tissue down to the target tissuesite and the gel administered (e.g., brushed, dripped, injected, orpainted, etc.) at or near the target site. In those embodiments wherethe drug depot is separate from the gel, first the cannula or needle canbe inserted through the skin and soft tissue down to the site ofinjection and one or more base layer(s) of gel can be administered tothe target site. Following administration of the one or more baselayer(s), the drug depot can be implanted on or in the base layer(s) sothat the gel can hold the depot in place or reduce migration. Ifrequired a subsequent layer or layers of gel can be applied on the drugdepot to surround the depot and further hold it in place. Alternatively,the drug depot may be implanted first and then the gel placed (e.g.,brushed, dripped, injected, or painted, etc.) around the drug depot tohold it in place. By using the gel, accurate and precise implantation ofa drug depot can be accomplished with minimal physical and psychologicaltrauma to the patient. The gel also avoids the need to suture the drugdepot to the target site reducing physical and psychological trauma tothe patient.

In various embodiments, when the target site comprises a spinal region,a portion of fluid (e.g., spinal fluid, etc.) can be withdrawn from thetarget site through the cannula or needle first and then the depotadministered (e.g., placed, dripped, injected, or implanted, etc.). Thetarget site will re-hydrate (e.g., replenishment of fluid) and thisaqueous environment will cause the drug to be released from the depot.

The at least one alpha adrenergic agonist formulation may be used toform different pharmaceutical preparations (e.g., drug depots,injectable formulations, etc.). The pharmaceutical preparations may beformed in and administered with a suitable pharmaceutical carrier thatmay be solid or liquid, and placed in the appropriate form forparenteral or other administration as desired. As persons of ordinaryskill are aware, known carriers include but are not limited to water,saline solution, gelatin, lactose, starches, stearic acid, magnesiumstearate, sicaryl alcohol, talc, vegetable oils, benzyl alcohols, gums,waxes, propylene glycol, polyalkylene glycols and other known carriers.

Another embodiment provides a method for treating a mammal sufferingfrom pain and/or inflammation, said method comprising administering atherapeutically effective amount of at least one alpha adrenergicagonist at or near the target site (e.g., herniated disc). The at leastone alpha adrenergic agonist may for example be administered locally tothe target tissue site as a drug depot.

In some embodiments, the therapeutically effective dosage amount (e.g.,alpha adrenergic agonist dose) and the release rate profile aresufficient to reduce inflammation and/or pain from one or moredegenerative discs for a period of at least one day, for example, 1-90days, 1-10 days, 1-3 days, 3-7 days, 3-12 days; 3-14 days, 7-10 days,7-14 days, 7-21 days, 7-30 days, 7-50 days, 7-90 days, 7-140 days,14-140 days, 3 days to 135 days, 3 days or 150 days, or 3 days to 6months.

In some embodiments the at least one alpha adrenergic agonist or aportion of the at least one alpha adrenergic agonist is administered asa bolus dose at the target tissue to provide an immediate release of thealpha adrenergic agonist.

In some embodiments there is a composition useful for the treatment ofinflammation comprising an effective amount of at least one alphaadrenergic agonist that is capable of being locally administered to atarget tissue site. By way of example, they may be administered locallyto the foraminal spine, the epidural space or the intrathecal space of aspinal cord. Exemplary administration routes include but are not limitedto catheter drug pumps, one or more local injections, polymer releasesor combinations thereof.

In some embodiments, the at least one alpha adrenergic agonist isadministered parenterally, e.g., by injection. In some embodiments, theinjection is intrathecal, which refers to an injection into the spinalcanal (intrathecal space surrounding the spinal cord). An injection mayalso be into a muscle or other tissue. In other embodiments, the alphaadrenergic agonist is administered by placement into an open patientcavity during surgery.

In some embodiments, the formulation is implantable into a surgical siteat the time of surgery. The active ingredients may then be released fromthe depot via diffusion in a sustained fashion over a period of time,e.g., 3-15 days, 5-10 days or 7-10 days post surgery in order to addresspain and/or inflammation resulting from a degenerative disc disease. Insome embodiments, the active ingredient may provide longer duration ofpain and/or inflammation relief for chronic diseases/conditions asdiscussed above with release of one or more drugs up to 6 months or 1year (e.g., 90, 100, 135, 150, 180 days or longer) resulting from adegenerative disc disease.

In some embodiments, the drug depot may release 5%, 10%, 15%, 20%, 25%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the at least one alphaadrenergic agonist or pharmaceutically acceptable salt thereof relativeto a total amount of at least one alpha adrenergic agonist loaded in thedrug depot over a period of 3 to 12 days, 5 to 10 days or 7 to 10 daysafter the drug depot is administered to the target tissue site. In someembodiments, the active ingredient may provide longer duration of painand/or inflammation relief for chronic diseases/conditions as discussedabove with release of one or more drugs up to 6 months or 1 year (e.g.,90, 100, 135, 150, 180 days or longer).

In various embodiments, an implantable drug depot useful for reducing,preventing or treating pain and/or inflammation is provided in a patientin need of such treatment, the implantable drug depot comprising atherapeutically effective amount of a alpha adrenergic agonist orpharmaceutically acceptable salts thereof, the depot being implantableat a site beneath the skin to reduce, prevent or treat pain and/orinflammation, resulting from a degenerative disc disease wherein thedrug depot (i) comprises one or more immediate release layer(s) that iscapable of releasing about 5% to about 20% of the alpha adrenergicagonist or pharmaceutically acceptable salts thereof relative to a totalamount of the alpha adrenergic agonist or pharmaceutically acceptablesalt thereof loaded in the drug depot over a first period of up to 48hours and (ii) one or more sustain release layer(s) that is capable ofreleasing about 21% to about 99% of the alpha adrenergic agonist orpharmaceutically acceptable salt thereof relative to a total amount ofthe alpha adrenergic agonist or pharmaceutically acceptable salt thereofloaded in the drug depot over a subsequent period of up to 3 days to 6months.

By way of non-limiting example, the target tissue site may comprise atleast one muscle, ligament, tendon, cartilage, spinal disc, spinalforaminal space near the spinal nerve root, facet or spinal canal. Alsoby way of example, the inflammation may be associated with orthopedic orspine surgery or a combination thereof. By way of further example, thesurgery may be arthroscopic surgery, an excision of a mass, herniateddisc repair, spinal fusion, thoracic, cervical, or lumbar surgery,pelvic surgery or a combination thereof. In some embodiments, the activeingredient may provide longer duration of pain and/or inflammationrelief for chronic diseases/conditions as discussed above with releaseof one or more drugs up to 6 months or 1 year (e.g., 90, 100, 135, 150,180 days or longer).

Degenerative Disc Disease

The human spine is formed from twenty-six consecutive vertebrae. Each ofthese vertebrae is separated from any adjacent vertebra by anintervertebral disc that functions to absorb shock and prevent eachvertebra from directly impacting upon another vertebra. At the center ofeach disc is a nucleus pulposus that contains proteoglycan. Around thenucleus pulposus is an outer ring called the annulus fibrosus.

Degenerative disc disease refers to any of the common degenerativeconditions of the spine involving degeneration of the disc. Discdegeneration is often associated with the symptom of pain and may leadto inflammation and neuropathic pain, for example, spinal stenosis,spondylolisthesis, and retrolisthesis.

Disc degeneration associated with the aging process is generallyassociated with the loss of proteoglycan from the nucleus pulposus ofthe spinal discs and a reduction of the disc's ability to absorb shockbetween vertebrae. Although some affected patients may not exhibitsymptoms, many affected patients suffer from chronic back and/or legpain. Pain associated with disc degeneration may become debilitating andmay greatly reduce a patient's quality of life.

As used herein, a “degenerative disc disease” means any condition whichresults in degeneration of an intervertebral disc, including but notlimited to, conditions caused by a disease, physical impact, mechanicalwear, a pathogen, or an autoimmune response.

Degenerative disc disease can occur anywhere in the spine, such as thecervical spine (the neck), the thoracic spine (the part of the backbehind the chest), the lumbar spine (lower back), and sacral spine (thepart connected to the pelvis that does not move). In embodiments claimedherein, the drug depot can be implanted at or near one or moredegenerative discs, for example, at the cervical, thoracic, lumbar,and/or sacral vertebrae.

In some embodiments, the degenerative disc disease can include anintervertebral disc herniation. As used herein “intervertebral discherniation” includes local displacement of disc material beyond thelimits of the intervertebral disc space. The disc material may benucleus pulposus, cartilage, fragmented apophysical bone, annular tissueor any combination thereof. Displacement of disc material may putpressure on the exiting spinal nerve and/or cause an inflammatoryreaction leading to radiculopathy, weakness, numbness, and/or tinglingin the arms or legs. Radiculopathy refers to any disease affecting thespinal nerve roots.

Intervertebral herniation can lead to conditions such as for example,sciatica, a compressed nerve, discogenic back pain, foraminal stenosis,pinched nerve, compressive neuropathy, chronic nerve pain, sensoryand/or motor neuropathy, numbness or weakness, or the like. Thus, thedrug depot of the present application can be used to treat thesediseases and/or conditions.

In some embodiments, intervertebral disc herniation includes a ruptureof the annulus fibrosis, through which the inner disc material (nucleuspulposus) extrudes, protrudes, bulges, migrates and/or re-herniates.Sometimes disc extrusions may be displaced so much that it has lostcontinuity with the parent disc. When this happens the extrusion iscalled sequestration. Thus, the drug depot of the present applicationcan be used to treat ruptures, protrusions, bulges, extrusions,re-herniation, and migration, fragmented, and/or sequestrated nucleuspulposus.

A “migrated disc or fragmented disc” refers to displacement of the discmaterial away from an opening in the annulus through which material hasextruded. Sometimes migrated fragments will be sequestrated. Forexample, the nucleus pulposus may migrate away from the herniated discso that there is sequestration in a different location in the spine thatmay lead to pinched nerve or spinal stenosis.

In general, most degenerative disc disease takes place in the lumbararea of the spine. Lumbar disc herniation occurs 15 times more oftenthan cervical disc herniation, and it is one of the most common causesof lower back pain. The cervical discs are affected 8% of the time andthe upper-to-mid-back (thoracic) discs only 1-2% of the time. Sometimesdegenerative disc disease can lead to compression of the nerve roots ofthe spine resulting in very painful neurological symptoms. Nerve roots(large nerves that branch out from the spinal cord) may becomecompressed resulting in neurological symptoms, such as sensory or motorchanges. For example herniation of the nucleus pulposus often isaccompanied by lower back pain that worsens in the sitting position andpain that radiates to the lower extremities. The radiating pain, forexample, in sciatica is often described as dull, burning or sharp pain,accompanied by intermittent sharp electric shock sensation, numbness,and tingling, motor or sensory defects of the respective nerve rootand/or reflex abnormalities.

In some embodiments, by implanting the drug depot containing the alphaadrenergic receptor agonist (e.g., clonidine) at or near the discherniation (e.g., within 5 cm) where the nucleus pulposus extrudes,protrudes or migrates out of the annulus, the alpha adrenergic receptoragonist as it elutes out of the drug depot can reduce the pain and/orinflammation associated with the disc herniation. In some embodiments,the alpha adrenergic agonist may cause enhanced resorption of thenucleus pulposus and reduces the size and volume of the nucleus pulposusherniation. In some embodiments, the size of the nucleus pulposusherniation is reduced and resorption is enhanced by about 15-20%,20-25%, 25-30%, 30-35%, 35-40%, 45-50%, 55-60%, 65-70%, 75-80%, 85-90%,or 95-100% or the herniated intervertebral disc completely resolves.

In some embodiments, by administering the alpha adrenergic receptoragonist, enhanced resorption of normal spontaneous resorption of thenucleus pulposus can occur by 15-20%, 20-25%, 25-30%, 30-35%, 35-40%,45-50%, 55-60%, 65-70%, 75-80%, 85-90%, or 95-100% above the amount thatwould occur due to normal spontaneous nucleus pulposus resorptionwithout treatment with an alpha adrenergic receptor agonist. Forexample, sometimes herniated nucleus pulposus will spontaneously resorbby itself without treatment. This typically can take about six weeks toeight weeks. By administering the alpha adrenergic agonist at or nearthe intervertebral herniation, in some embodiments of the presentapplication, the resorption of the nucleus pulposus will be enhanced orincrease so that the herniation will heal faster than without anytreatment.

In some embodiments, by implanting the drug depot at or near the discherniation, the size and/or volume of the nucleus pulposus herniation isreduced by ⅕, ¼, ⅓, ½, ⅔, ¾ or completely. For example, the drug depotcan be implanted within the herniation, 0.01 cm, 0.1 cm, 0.5 cm, 1 cm, 2cm, 3 cm, 4 cm, 5 cm away from the disc herniation and the size and/orvolume will decrease by ⅕, ¼, ⅓, ½, ⅔, ¾ or completely within a certaintime period (e.g., 3 days to 6 months, 3 days to 8 weeks, or 6 weeks to3 months).

In some embodiments, the alpha adrenergic agonist (e.g., clonidine) willreverse, reduce, and/or inhibit the progression and/or severity ofintervertebral disc herniation, or reduce the severity of one or moresymptoms of intervertebral disc herniation (e.g., pain, numbness,tingling, motor or sensory defects, etc.).

In some embodiments, the reduction of the intervertebral disc herniationcan be determined clinically by improvement in the patient's signs andsymptoms (e.g., reduced back pain, numbness, etc.). In some embodiments,the reduction of the intervertebral disc herniation can be determined bymeasuring size and/or volume reduction of the nucleus pulposus bydiagnostic tests such as for example, x-ray, CT, MRI, myelogram,electromyogram, nerve conduction studies, or the like.

In some embodiments, a method is provided for treating a degenerativedisc in a patient in need of such treatment, the method comprisingadministering one or more biodegradable drug depots comprising atherapeutically effective amount of an alpha adrenergic agonist at ornear the degenerative disc, wherein the one or more biodegradable drugdepot is capable of releasing an effective amount of the alphaadrenergic receptor agonist over a period of at least 3 days to 6months.

For purposes of illustration only, FIG. 1A illustrates an example of adegenerative disc disease involving an intervertebral disc 20 a. Theintervertebral disc 20 a is made up of two components: the annulusfibrosus 22 a and the nucleus pulposus 24 a. The nucleus pulposus 24 ais the inner gelatinous material surrounded by the annulus fibrosus. Itdistributes mechanical loads placed upon the disc 20 a, while theannulus fibrosus 22 a provides structural integrity and constrains thenucleus pulposus 24 a to a specific spinal region. The annulus fibrosus22 a is designed with fibrocartilaginous and fibrous tissue arranged inconcentric layers called laminae. As one moves, from the nucleuspulposus to the periphery, the annulus fibrosus tissue becomes denser,stronger, less elastic, less fluid, and more ligamentous until reachingthe outermost layers. There, the tissue actually becomes a tough,capsular ligament. The annulus fibrosus 22 a can become weaker anddegenerate with age, and may begin to tear. As shown in FIG. 1A, defectsin the annulus fibrosus called annular tears, 22 a allow bulging orherniation 26 of the nucleus pulposus in the early stages. As timeprogresses and the disc degenerates, as shown in FIG. 1B, it often leadsto a complete rupturing 28 of the annulus fibrosus 22 a and 22 b. Theherniated 20 a or ruptured 20 b disc compresses the spinal canal andexerts pressure on the nerve roots that pass through the disc 20 a, 20 bcausing lower back pain. In addition, the nucleus pulposus 24 a containssignificant amounts of substances capable of exciting, or increasing theexcitability of, sensory nerves such as prostaglandin E, histamine-likesubstances, lactic acid and polypeptide amines. These substances mayescape through the annular tears 28, increasing the lower back pain,sciatica, or result in radiating leg pain. In addition, the annulartears 25 a and 25 b cause fibrous tissue to grow in the tear, whichincreases pain and/or inflammation.

A drug depot containing the alpha adrenergic receptor agonist can beimplanted at or near the disc herniation. For example, at or near theannular tear (e.g., within 1 cm of it). This will reduce the pain and/orinflammation associated with the herniated disc.

FIG. 2 illustrates an example of a degenerative disc disease shown as anintervertebral disc 30 having annular tears 34 a and 34 b in annulusfibrosis 32. However, this intervertebral disc is not ruptured, as thenucleus pulposus 31 is contained at this stage as a result of theimplantation of the drug depot. The drug depot 10 is delivered (via asyringe 36 through a needle 38 using plunger 37) into tissue adjacent totears 34 a and 34 b. The drug depot may be injected into the tissuewithin about 1 cm, 2 cm, or 5 cm or 10 cm of the defect, where depotwill catch the adjacent tissue 39 and the depot will be at or near theannular tears 34 a and 34 b. In this way, target directed delivery ofthe drug can be accomplished.

In some embodiments, the closer the drug depot is delivered to theherniation, the more the enhancement of nucleus pulposus resorption willoccur and the more there will be a reduction in intervertebral discherniation. “Reducing intervertebral disc herniations” refers toadministering a composition so as to cause a reduction in the number ofintervertebral disc herniations, extent of intervertebral discherniations (e.g., area), and/or severity of intervertebral discherniations (e.g., thickness, volume) relative to the number, extent,and/or severity of intervertebral disc herniations that would occurwithout such administration. In various embodiments, reducingintervertebral disc herniations may be part of a protocol and alsoinclude performing a procedure (e.g., subsequent surgery to reduceintervertebral disc herniations). The composition or procedure mayinhibit formation of intervertebral disc herniation following anintervertebral disc herniation promoting stimulus, may inhibitprogression of intervertebral disc herniation, and/or may inhibitrecurrence of intervertebral disc herniation. In some embodiments,reducing the disc herniation includes decrease in the signs and/orsymptoms of the disc herniation, including a decrease in the pain and/orinflammation associated with the disc herniation.

“Preventing intervertebral disc herniations” refers to administering atherapeutic composition prior to formation of intervertebral discherniations in order to reduce the likelihood that intervertebral discherniations will form in response to a particular insult, stimulus, orcondition. In various embodiments, preventing intervertebral discherniations may be part of a protocol and also include performing aprocedure (e.g., surgery to reduce intervertebral disc herniations). Itwill be appreciated that “preventing intervertebral disc herniations”does not require that the likelihood of intervertebral disc herniationformation is reduced to zero. Instead, “preventing intervertebral discherniations” refers to a clinically significant reduction in thelikelihood of intervertebral disc herniation formation following aparticular insult or stimulus, e.g., a clinically significant reductionin the incidence or number of intervertebral disc herniations inresponse to a particular intervertebral disc herniation promotinginsult, condition, or stimulus.

“Treating intervertebral disc herniations,” refers to administering acomposition that reverses (completely or partially), alleviates,reduces, and/or inhibits the progression and/or severity ofintervertebral disc herniations, or reduces the likelihood of recurrenceand/or the severity of recurrent intervertebral disc herniations.“Treating intervertebral disc herniations” also refers to administeringa composition that reverses, alleviates, reduces, inhibits theprogression of, or reduces the likelihood of recurrence and/or severityof one or more symptoms of intervertebral disc herniations (e.g., pain,numbness, tingling, inflammation, sciatica, etc.). In variousembodiments, treating intervertebral disc herniations may be part of aprotocol and also include performing a procedure (e.g., surgery toreduce intervertebral disc herniations). Thus “treating intervertebraldisc herniations” involves administering a therapeutic compositionand/or procedure once intervertebral disc herniation(s) have alreadyformed following an insult or stimulus.

The term “pain” includes nociception and the sensation of pain, both ofwhich can be assessed objectively and subjectively, using pain scoresand other methods well-known in the art. Exemplary types of painreducible, preventable or treatable by the methods and compositionsdisclosed herein include, without limitation, lower back pain, facetjoint pain, neck pain, leg pain, radicular pain, neuropathic pain of thearm, neck, back, lower back, leg, or related pain distributionsresulting from disc or spine surgery.

Although the spinal site is shown, as described above, the drug depotcan be delivered to any site beneath the skin, including, but notlimited to, at least one muscle, ligament, tendon, cartilage, spinaldisc, spinal foraminal space, near the spinal nerve root, facet joint,or spinal canal.

In some embodiments, for treatment of degenerative disc disease and/orfacet joint pain, the drug depot containing the alpha adrenergic agonist(e.g., clonidine) can be implanted locally at or near the site ofinflammation and/or pain and the drug depot will release the clonidinefor at least one day to at least 6 to 12 months.

In some embodiments, the alpha adrenergic receptor agonist (e.g.,clonidine) can be administered at or near the facet joint of the spine.Facet joints are small joints at each segment of the spine that providestability and help guide motion. The facet joints can become painful dueto arthritis of the spine, a back injury or mechanical stress to theback, and/or inflammation at the facet joint. A drug depot can beimplanted at or near the cervical (neck), thoracic (upper back), and/orlumbar (lower back) facet joint so as to treat, reduce and/or preventback pain and/or inflammation. For example, the drug depot containingthe alpha adrenergic receptor agonist can be implanted at or near(within about 5 cm, or within about 2 cm, or within 0.1 cm for example)from the affected facet joint. In this way local treatment of the facetjoint is provided.

By administering the alpha adrenergic receptor agonist in the drug depot(e.g., clonidine) locally at or near the site of pain or inflammation(e.g., spinal site, degenerative disc, annulus, facet joint, etc.), onecan effectively reduce, prevent or treat degenerative disc diseaseand/or facet joint pain for extended periods of time. The drug depot mayrelease the alpha adrenergic agonist over a period of 1-90 days, 1-10days, 1-3 days, 3-7 days, 3-12 days; 3-14 days, 7-10 days, 7-14 days,7-21 days, 7-30 days, 7-50 days, 7-90 days, 7-140 days, 14-140 days, 3days to 135 days, 3 days to 150 days, or 3 days to 6 months.

In some embodiments, the at least one alpha adrenergic agonist orpharmaceutically acceptable salt thereof is encapsulated in a pluralityof depots comprising microparticles, microspheres, microcapsules, and/ormicrofibers suspended in a gel.

In some embodiments, a method is provided of inhibiting pain and/orinflammation from degenerative disc disease in a patient in need of suchtreatment, the method comprising delivering one or more biodegradabledrug depots comprising a therapeutically effective amount of at leastone alpha adrenergic agonist or pharmaceutically acceptable salt thereofto a target tissue site beneath the skin before, during or aftersurgery, wherein the drug depot releases an effective amount of at leastone alpha adrenergic agonist or pharmaceutically acceptable salt thereofover a period of 3 days to 6 months.

In some embodiments, an implantable drug depot useful for preventing ortreating pain and/or inflammation in a patient in need of such treatmentis provided, the implantable drug depot comprising a therapeuticallyeffective amount of at least one alpha adrenergic agonist orpharmaceutically acceptable salt thereof, the depot being implantable ata site beneath the skin to prevent or treat inflammation, wherein thedrug depot releases an effective amount of at least one alpha adrenergicagonist or pharmaceutically acceptable salt thereof over a period of 33days to 6 months.

In some embodiments, an implantable drug depot is provided, wherein thedrug depot (i) comprises one or more immediate release layer(s) thatreleases a bolus dose of at least one alpha adrenergic agonist orpharmaceutically acceptable salt thereof at a site beneath the skin and(ii) one or more sustain release layer(s) that releases an effectiveamount of at least one alpha adrenergic agonist or pharmaceuticallyacceptable salt thereof over a period of 3 to 12 days or 5 to 10 days or7 to 10 days or 3 days to 6 months. By way of example, in the drugdepot, the one or more immediate release layer(s) may comprisepoly(lactide-co-glycolide) (PLGA) and the one or more sustain releaselayer(s) may comprise polylactide (PLA).

Method of Making

In various embodiments, the drug depot comprising the active ingredients(e.g., alpha agonist) can be made by combining a biocompatible polymerand a therapeutically effective amount of the active ingredients orpharmaceutically acceptable salts thereof and forming the implantabledrug depot from the combination.

Various techniques are available for forming at least a portion of adrug depot from the biocompatible polymer(s), therapeutic agent(s), andoptional materials, including solution processing techniques and/orthermoplastic processing techniques. Where solution processingtechniques are used, a solvent system is typically selected thatcontains one or more solvent species. The solvent system is generally agood solvent for at least one component of interest, for example,biocompatible polymer and/or therapeutic agent. The particular solventspecies that make up the solvent system can also be selected based onother characteristics, including drying rate and surface tension.

Solution processing techniques include solvent casting techniques, spincoating techniques, web coating techniques, solvent spraying techniques,dipping techniques, techniques involving coating via mechanicalsuspension, including air suspension (e.g., fluidized coating), ink jettechniques and electrostatic techniques. Where appropriate, techniquessuch as those listed above can be repeated or combined to build up thedepot to obtain the desired release rate and desired thickness.

In various embodiments, a solution containing solvent and biocompatiblepolymer are combined and placed in a mold of the desired size and shape.In this way, polymeric regions, including barrier layers, lubriciouslayers, and so forth can be formed. If desired, the solution can furthercomprise, one or more of the following: other therapeutic agent(s) andother optional additives such as radiographic agent(s), etc. indissolved or dispersed form. This results in a polymeric matrix regioncontaining these species after solvent removal. In other embodiments, asolution containing solvent with dissolved or dispersed therapeuticagent is applied to a pre-existing polymeric region, which can be formedusing a variety of techniques including solution processing andthermoplastic processing techniques, whereupon the therapeutic agent isimbibed into the polymeric region.

Thermoplastic processing techniques for forming the depot or portionsthereof include molding techniques (for example, injection molding,rotational molding, and so forth), extrusion techniques (for example,extrusion, co-extrusion, multi-layer extrusion, and so forth) andcasting.

Thermoplastic processing in accordance with various embodimentscomprises mixing or compounding, in one or more stages, thebiocompatible polymer(s) and one or more of the following: the activeingredients (e.g., alpha agonist), optional additional therapeuticagent(s), radiographic agent(s), and so forth. The resulting mixture isthen shaped into an implantable drug depot. The mixing and shapingoperations may be performed using any of the conventional devices knownin the art for such purposes.

During thermoplastic processing, there exists the potential for thetherapeutic agent(s) to degrade, for example, due to elevatedtemperatures and/or mechanical shear that are associated with suchprocessing. For example, certain therapeutic agents may undergosubstantial degradation under ordinary thermoplastic processingconditions. Hence, processing is preferably performed under modifiedconditions, which prevent the substantial degradation of the therapeuticagent(s). Although it is understood that some degradation may beunavoidable during thermoplastic processing, degradation is generallylimited to 10% or less. Among the processing conditions that may becontrolled during processing to avoid substantial degradation of thetherapeutic agent(s) are temperature, applied shear rate, applied shearstress, residence time of the mixture containing the therapeutic agent,and the technique by which the polymeric material and the therapeuticagent(s) are mixed.

Mixing or compounding biocompatible polymer with therapeutic agent(s)and any additional additives to form a substantially homogenous mixturethereof may be performed with any device known in the art andconventionally used for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formedby heating the biocompatible polymer, which can be mixed with variousadditives (e.g., therapeutic agent(s), inactive ingredients, etc.) toform a mixture. A common way of doing so is to apply mechanical shear toa mixture of the biocompatible polymer(s) and additive(s). Devices inwhich the biocompatible polymer(s) and additive(s) may be mixed in thisfashion include devices such as single screw extruders, twin screwextruders, banbury mixers, high-speed mixers, ross kettles, and soforth.

Any of the biocompatible polymer(s) and various additives may bepremixed prior to a final thermoplastic mixing and shaping process, ifdesired (e.g., to prevent substantial degradation of the therapeuticagent among other reasons).

For example, in various embodiments, a biocompatible polymer isprecompounded with a radiographic agent (e.g., radio-opacifying agent)under conditions of temperature and mechanical shear that would resultin substantial degradation of the therapeutic agent, if it were present.This precompounded material is then mixed with therapeutic agent (e.g.,alpha agonist) under conditions of lower temperature and mechanicalshear, and the resulting mixture is shaped into the active ingredientcontaining drug depot. Conversely, in another embodiment, thebiocompatible polymer can be precompounded with the therapeutic agentunder conditions of reduced temperature and mechanical shear. Thisprecompounded material is then mixed with, for example, aradio-opacifying agent, also under conditions of reduced temperature andmechanical shear, and the resulting mixture is shaped into the drugdepot.

The conditions used to achieve a mixture of the biocompatible polymerand therapeutic agent and other additives will depend on a number offactors including, for example, the specific biocompatible polymer(s)and additive(s) used, as well as the type of mixing device used.

As an example, different biocompatible polymers will typically soften tofacilitate mixing at different temperatures. For instance, where a depotis formed comprising PLGA or PLA polymer, a radio-opacifying agent(e.g., bismuth subcarbonate), and a therapeutic agent prone todegradation by heat and/or mechanical shear (e.g., clonidine), invarious embodiments, the PGLA or PLA can be premixed with theradio-opacifying agent at temperatures of about, for example, 150° C. to170° C. The therapeutic agent is then combined with the premixedcomposition and subjected to further thermoplastic processing atconditions of temperature and mechanical shear that are substantiallylower than is typical for PGLA or PLA compositions. For example, whereextruders are used, barrel temperature, volumetric output are typicallycontrolled to limit the shear and therefore to prevent substantialdegradation of the therapeutic agent(s). For instance, the therapeuticagent and premixed composition can be mixed/compounded using a twinscrew extruder at substantially lower temperatures (e.g., 100-105° C.),and using substantially reduced volumetric output (e.g., less than 30%of full capacity, which generally corresponds to a volumetric output ofless than 200 cc/min). It is noted that this processing temperature iswell below the melting points of certain active ingredients, such as ananti-inflammatory and analgesic (e.g., clonidine) because processing ator above these temperatures will result in substantial therapeutic agentdegradation. It is further noted that in certain embodiments, theprocessing temperature will be below the melting point of all bioactivecompounds within the composition, including the therapeutic agent. Aftercompounding, the resulting depot is shaped into the desired form, alsounder conditions of reduced temperature and shear.

In other embodiments, biodegradable polymer(s) and one or moretherapeutic agents are premixed using non-thermoplastic techniques. Forexample, the biocompatible polymer can be dissolved in a solvent systemcontaining one or more solvent species. Any desired agents (for example,a radio-opacifying agent, a therapeutic agent, or both radio-opacifyingagent and therapeutic agent) can also be dissolved or dispersed in thesolvents system. Solvent is then removed from the resultingsolution/dispersion, forming a solid material. The resulting solidmaterial can then be granulated for further thermoplastic processing(for example, extrusion) if desired.

As another example, the therapeutic agent can be dissolved or dispersedin a solvent system, which is then applied to a pre-existing drug depot(the pre-existing drug depot can be formed using a variety of techniquesincluding solution and thermoplastic processing techniques, and it cancomprise a variety of additives including a radio-opacifying agentand/or viscosity enhancing agent), whereupon the therapeutic agent isimbibed on or in the drug depot. As above, the resulting solid materialcan then be granulated for further processing, if desired.

Typically, an extrusion processes may be used to form the drug depotcomprising a biocompatible polymer(s), therapeutic agent(s) andradio-opacifying agent(s). Co-extrusion may also be employed, which is ashaping process that can be used to produce a drug depot comprising thesame or different layers or regions (for example, a structure comprisingone or more polymeric matrix layers or regions that have permeability tofluids to allow immediate and/or sustained drug release). Multi-regiondepots can also be formed by other processing and shaping techniquessuch as co-injection or sequential injection molding technology.

In various embodiments, the depot that may emerge from the thermoplasticprocessing (e.g., pellet, strip, etc.) is cooled. Examples of coolingprocesses include air cooling and/or immersion in a cooling bath. Insome embodiments, a water bath is used to cool the extruded depot.However, where a water-soluble therapeutic agent such as activeingredients are used, the immersion time should be held to a minimum toavoid unnecessary loss of therapeutic agent into the bath.

In various embodiments, immediate removal of water or moisture by use ofambient or warm air jets after exiting the bath will also preventre-crystallization of the drug on the depot surface, thus controlling orminimizing a high drug dose “initial burst” or “bolus dose” uponimplantation or insertion if this is release profile is not desired.

In various embodiments, the drug depot can be prepared by mixing orspraying the drug with the polymer and then molding the depot to thedesired shape. In various embodiments, active ingredients are used andmixed or sprayed with the PLGA or PEG550 polymer, and the resultingdepot may be formed by extrusion and dried.

The drug depot may also be made by combining a biocompatible polymer anda therapeutically effective amount of at least one alpha adrenergicagonist or pharmaceutically acceptable salt thereof and forming theimplantable drug depot from the combination.

Having now generally described the invention, the same may be morereadily understood through the following reference to the followingexamples, which are provided by way of illustration and are not intendedto limit the present invention unless specified.

EXAMPLES

The examples below show certain particularly advantageous resultswherein the initial burst is not too large (i.e., not more than 7% ofthe load drug in the first five days) and the daily does isapproximately 2.4 μg/day±0.5 μg/day for 135 days. See e.g., FIGS. 10 and11; 14; and 19. The figures further demonstrate that drug loadings 5 wt.% to 8 wt. % provide advantageous results.

A 2-month chronic constriction injury (CCI) model of neuropathic painwas used to evaluate different formulations of a corticosteroid,fluocinolone, encapsulated in bioerodable polymers compared tofluocinolone given subcutaneously (SC). Different formulations asprovided in Table 5 below were evaluated for reducing pain-associatedbehaviors: Thermal paw withdrawal latency was evaluated at baseline 7,14, 21, 28, 35, 42, 49, 56 and 64 days post-operatively, whilemechanical threshold was evaluated at 8, 15, 22, 29, 36, 43, 50, 57 and64 days post-operatively. Bar graphs depicting the results of thesestests are shown in FIGS. 3-4.

The In-Vitro Elution. Studies were carried out at 37° C. inphosphate-buffered saline (PBS, pH 7.4). Briefly, the rods (n=3) wereweighed prior to immersion in 5 mL of PBS. At regular time intervals,the PBS was removed for analysis and replaced with 5 mL of fresh PBS.The PBS-elution buffer was analyzed for clonidine content using UV-Visspectrometry.

Example 1 Formulation Testing

The inventors prepared a number of clonidine formulations in which theyvaried the polymer type, drug load, excipient (including someformulations in which there was no excipient), pellet size andprocessing. These formulations are described below in Table 1, Table 2and Table 3. A number of tests were performed on these formulations,including in vitro release tests in which the number of microgramsreleased was measured, as well as the cumulative percentage release ofclonidine. The results of these tests appear in FIGS. 7-36.

The In-Vitro Elution Studies were carried out at 37° C. inphosphate-buffered saline (PBS, pH 7.4). The rods (n=3) were weighedprior to immersion in 5 mL of PBS. At regular time intervals, the PBSwas removed for analysis and replaced with 5 mL of fresh PBS. ThePBS-elution buffer was analyzed for clonidine content using UV-Visspectrometry.

TABLE 1 Drug Pellet Size Load (L × Dia; mm) or Notebook ID Polymer Type(Wt %) Excipient Description Processing 13335-60-1 8515 DLG 7E 10 N/A0.75 × 0.75 Melt extrusion, co-spray dried drug/polymer 13335-60-2 8515DLG 7E 10 N/A 0.75 × 0.75 Melt extrusion, spray dried drug 13335-60-38515 DLG 7E 10 N/A 0.75 × 0.75 Melt extrusion, hand ground drug13335-60-4 8515 DLG 7E 10 N/A 0.75 × 0.75 Melt extrusion, hand grounddrug, spray dried polymer 13335-60-5 8515 DLG 7E 10 N/A 0.75 × 0.75 Meltextrusion w/ recycle loop, hand ground drug 13335-65-1 8515 DLG 7E 5 N/A 3.0 × 0.75 Melt extrusion, spray dried drug 13335-65-2 8515 DLG 7E 10N/A  1.5 × 0.75 Melt extrusion, spray dried drug 13335-65-3 8515 DLG 7E20 N/A 0.75 × 0.75 Melt extrusion, spray dried drug 13335-65-4 100 DL 7E5 N/A  3.0 × 0.75 Melt extrusion, spray dried drug 13335-65-5 100 DL 7E10 N/A  1.5 × 0.75 Melt extrusion, spray dried drug 13335-65-6 100 DL 7E20 N/A 0.75 × 0.75 Melt extrusion, spray dried drug 13335-97-1 8515 DLG7E 7.5 N/A  3.0 × 0.75 Melt extrusion, spray dried drug 13335-97-2 100DL 7E 5 N/A  3.0 × 0.75 Melt extrusion, spray dried drug 13335-97-3 8515DLG 7E 5  10% mPEG  3.0 × 0.75 Melt extrusion, spray dried drug13335-97-4 100 DL 7E 5  10% mPEG  3.0 × 0.75 Melt extrusion, spray drieddrug 13699-1-1 100 DL 7E 5 N/A  3.0 × 0.75 Melt extrusion, spray drieddrug 13699-16-1 8515 DLG 7E 10 N/A  1.5 × 0.75 Melt extrusion, spraydried drug 13699-16-2 9010 DLG 7E 10 N/A  1.5 × 0.75 Melt extrusion,spray dried drug 13699-16-3 9010 DLG 7E 5 N/A  3.0 × 0.75 Meltextrusion, spray dried drug 13699-16-4 8515 DLG 7E 5   5% mPEG  3.0 ×0.75 Melt extrusion, spray dried drug 13699-16-5 8515 DLG 7E 5 2.5%  3.0× 0.75 Melt extrusion, spray dried drug mPEG 13699-20-1 8515 DLG 7E 5  1% MgO  3.0 × 0.75 Melt extrusion, spray dried drug 13699-20-4 8515DLG 7E 5 N/A  3.0 × 0.75 Melt extrusion, spray dried drug 13699-20-5 100DL 7E 5  10% 5050  3.0 × 0.75 Melt extrusion, spray dried drug DLG 6E13699-20-6 100 DL 7E 5  10% 5050  3.0 × 0.75 Melt extrusion, spray drieddrug DLG 1A 13699-20-7 8515 DLG 10 N/A  1.5 × 0.75 Melt extrusion, spraydried drug Purac 13699-20-8 8515 DLG 7E 5 N/A  3.0 × 0.75 Melt extrusion2X, spray dried drug 13699-28-1 8515 DLG 7.5 N/A 3.0 × 7.5 Meltextrusion, spray dried drug Purac 13699-28-2 8516 DLG 12.5 N/A  2.0 ×0.75 Melt extrusion, spray dried drug Purac 13699-28-3 100 DL 7E 5 N/A 3.0 × 0.75 Melt extrusion, spray dried drug 13699-31-1 8515 DLG 7E 10N/A N/A heat press, spray dried drug 13699-31-2 8515 DLG 7E 10 N/A N/Aheat press, spray dried drug 13699-31-3 8515 DLG 7E 10 N/A N/A heatpress, spray dried drug 13699-31-4 8515 DLG 7E 10 N/A N/A Meltextrusion, spray dried drug 12702-13-4-a 1,6- 10 N/A 3 × 3 Meltextrusion Hexanediol/ tCHDM 12702-13-4-b 75/25 PLGA 10 N/A 3 × 3 Meltextrusion 12702-68-12 75/25 PLGA 5 mPEG 1 × 1 Melt extrusion 12702-68-1375/25 PLGA 5 TBO-Ac 1 × 1 Melt extrusion 12702-72-1 75/25 PLGA 5 mPEG 1× 1 Melt extrusion 12702-80-7 75/25 PLGA 10 mPEG 0.75 × 0.75 Meltextrusion 12702-80-8 75/25 PLGA 15 mPEG 0.75 × 0.75 Melt extrusion13395-3-1 85/15 PLGA 10 mPEG 0.75 × 0.75 Melt extrusion 13395-3-2 85/15PLGA 15 mPEG 0.75 × 0.75 Melt extrusion 13395-3-3 85/15 PLGA 5 mPEG 0.75× 0.75 Melt extrusion 13395-15 85/15 PLGA 15 mPEG 0.75 × 0.75 Meltextrusion 13395-20-1 85/15 PLGA 5 Span-85 0.75 × 0.75 Melt extrusion13395-20-2 85/15 PLGA 5 Pluronic- 0.75 × 0.75 Melt extrusion F12713395-20-3 85/15 PLGA 5 N/A 0.75 × 0.75 Melt extrusion 13395-21-1D,L-PLA 5 mPEG 0.75 × 0.75 Melt extrusion 13395-21-2 85/15 PLGA 5 TBO-Ac0.75 × 0.75 Melt extrusion 13395-24-1 85/15 PLGA 5 Span-65 0.75 × 0.75Melt extrusion 13395-27-1 85/15 PLGA 10 N/A 0.75 × 0.75 Melt extrusion13395-27-2 85/15 PLGA 15 N/A 0.75 × 0.75 Melt extrusion 13395-27-3 85/15PLGA 10 Span-65 0.75 × 0.75 Melt extrusion 13395-27-4 85/15 PLGA 10TBO-Ac 0.75 × 0.75 Melt extrusion 13395-27-5 85/15 PLGA 10 Pluronic 0.75× 0.75 Melt extrusion F127 13395-34-2 D,L-PLA 10 N/A 0.75 × 0.75 Meltextrusion 13395-34-3 D,L-PLA 10 TBO-Ac 0.75 × 0.75 Melt extrusion13395-34-4 D,L-PLA 10 mPEG 0.75 × 0.75 Melt extrusion 13395-42-1DL-PLA/PCL 10 N/A 0.75 × 0.75 Melt extrusion 13395-42-2 DL-PLA/PCL 15N/A 0.75 × 0.75 Melt extrusion

TABLE 2 Drug Load Pellet Size (L × Dia; Notebook ID Polymer Type (Wt %)Excipient mm) or Description Processing 13335-73-1 POE 58 10 N/A  1.5 ×0.75 Melt extrusion 13335-73-2 POE 58 20 N/A 0.75 × 0.75 Melt extrusion13335-73-3 POE 60 10 N/A  1.5 × 0.75 Melt extrusion 13335-73-4 POE 60 20N/A 0.75 × 0.75 Melt extrusion 13699-1-2 POE 58 10 N/A 4-1.5 × 0.75 Melt extrusion 13699-1-3 POE 58 20 N/A 1-0.75 × 0.75   Melt extrusion12702-23 tCHDM (100) 25 N/A Microspheres Double emulsion 12702-26tCHDM/DET 4.2 N/A Microspheres Double emulsion (70/30) 12702-54 75/25PLGA 20 N/A Microspheres Double emulsion 12702-68-9 75/25 PLGA 5 mPEG 3× 3 Melt extrusion 12702-68-10 75/25 PLGA 5 TBO-Ac 3 × 3 Melt extrusion12702-87 75/25 PLGA 15 mPEG Mixer-Molder 12702-90 85/15 PLGA 17 N/AMixer-Molder 12702-78-1 Polyketal 7 N/A 2 × 3 Melt extrusion(12833-14-1) 13395-14 50/50 PLGA 10 mPEG N/A Melt extrusion (2A)13395-17-1 POE (13166- 5 N/A 1.5 × 1.5 Melt extrusion 75) 13395-17-2 POE(13166- 5 N/A 1.5 × 1.5 Melt extrusion 77) 13395-47-1 DL-PCL 10 N/A 1.3× 1.3 Melt extrusion 13395-50 DL-PCL 10 N/A 1.3 × 1.3 Melt extrusion; w/solvent prep 13395-51 D,L-PLA 10 mPEG N/A Melt extrusion

TABLE 3 Drug Load Notebook ID Polymer Type (Wt %) Processing 00178-23100 DL 5E 8.1 Grind drug with mortar/pestile, blend with spatula,coarsely mixed 00178-15 100 DL 7E 7.2 Grind drug with mortar/pestile,blend with spatula, coarsely mixed 00178-35 100 DL 5E 5 Grind drug withmortar/pestile, blend with spatula, coarsely mixed 00178-16 100 DL 7E10.2 Grind drug with mortar/pestile, blend with spatula, coarsely mixed00178-21 8515 DL 7E 7.3 Grind drug with mortar/pestile, blend withspatula, coarsely mixed 00178-36 100 DL 7E 5 Grind drug withmortar/pestile, blend with spatula, coarsely mixed 00178-44 100 DL 7E5.1 Dissolved in glacial acetic acid and freeze dried 00178-45 100 DL 7E4.5 Drug and polymer blended by mortar/pestile, finely mixed, under N200178-63 100 DL 7E 9.4 Drug and polymer blended by mortar/pestle, finelymixed 00178-08 100 DL 7E 21.4 Blend with spatula, no reduction in drugparticle size 00178-11 100 DL 7E 7.9 Blend with spatula, no reduction indrug particle size 00178-12 100 DL 7E 11.7 Blend with spatula, noreduction in drug particle size 00178-22 8515 DL 7E 83.3 Grind drug withmortar/pestile, blend with spatula, coarsely mixed 00178-24 100 DL 5E10.1 Grind drug with mortar/pestile, blend with spatula, coarsely mixedtab 11 100 DL 5E 5 tab 11 100 DL 7E 5 tab 11 100 DL 5E 5 EtOAc coatingtab 11 100 DL 7E 5 EtOAc coating tab 11 100 DL 7E 5 Glacial HoAcdissolution tab 11 100 DL 7E 5 prepared in N2 environment 00178-72 100DL 7E 4.5 Double Extrusion (20% diluted to 5%) 00178-73 100 DL 7E 8.7Double Extrusion (20% diluted to 10%) 00178-74 100 DLG 7E 7.3 API mixedwith polymer using mortar/pestle 00178-71 6535 DLG 7E 5.3 API mixed withpolymer using mortar/pestle 00178-75 6535 DLG 7E 5.3 API mixed withpolymer using mortar/pestle 00178-76-R1 100 DL 7E core with 7.76 coaxialextrusion, 4 different coating thicknesses 100DL coating 00178-76-R2 101DL 7E core 6.92 coaxial extrusion, 4 different coating thicknesses with100DL coating 00178-76-R3 102 DL 7E core 6.76 coaxial extrusion, 4different coating thicknesses with 100DL coating 00178-76-R4 103 DL 7Ecore 8 coaxial extrusion, 4 different coating thicknesses with 100DLcoating 00178-79-R1 100 DL 5E core with 15 coaxial extrusion, thin coat100DL 5E coating 00178-79-R2 100 DL 5E core with 15 coaxial extrusion,thick coat 100DL 5E coating 00178-80-R1 100 DL 5E core with 7.54 coaxialextrusion, different coating thicknesses 100DL 5E coating 00178-80-R2100 DL 5E core with 8.9 coaxial extrusion, different coating thicknesses100DL 5E coating 00178-80-R3 100 DL 5E core with 9.39 coaxial extrusion,different coating thicknesses 100DL 5E coating 00178-77 100 DL 5E 5repeat of 178-35 (0.8 MM & 1.0 mm diam) 00178-78 100 DL 5E 5 repeat of178-35 (0.8 MM & 1.0 mm diam) 00178-81 100 DL 5E 7.2 repeat of 178-2300178-23B EtOAc coating 00178-23C Polymer soln coating

The codes within the table for the polymer are explained as follows. Thefirst number or numbers refer to monomer mole percentage ratio ofDL-lactide (e.g., polylactide) to glycolide (e.g., poly-glycolide). Theletter code that follows the first number refers to the polymer(s) andis the polymer identifier. The second number, which follows the lettercode for the polymer, is the target IV designator and is 10 times themidpoint of a range in dl/g. The meanings of certain IV designators arereflected in Table 4.

TABLE 4 IV Target Designator IV Range 1 0.05-0.15 1.5 0.10-0.20 20.15-0.25 2.5 0.20-0.30 3 0.25-0.35 3.5 0.30-0.40 4 0.35-0.45 4.50.40-0.50 5 0.45-0.55 6 0.50-0.70 7 0.60-0.80 8 0.70-0.90 9 0.80-1.0

The final letter within the code of the polymer is the end groupdesignator. For examples “E” refers to an ester end group, while “A”refers to an acid end group.

By way of example, 100 DL 7E is a polymer that has an inherent viscosityof 0.60-0.80 dL/g. It contains 100% poly(DL-lactide) that has ester endgroups. It is available from Lakeshore Biomaterials, Birmingham, Ala.

Example 2

The inventors evaluated the efficacy of a five Month Clonidine/PolymerDrug Depot in the Rat Chronic Constriction Injury Model. The animalmodel was the Bennett Model (Wistar rat). The purpose: To determinewhether a five month polymer clonidine-eluting depot can improve painassociated behavioral responses in a rat model of neuropathic pain.

Experimental Design: Four loose chromic gut ligatures, 1 mm apart, weretied around the common sciatic nerve at mid-thigh. Each animal receivedtreatment of test or control article-according to the dosing describedin Table 5.

TABLE 5 Group Number Treatment Dose Comments 1 Clonidine 0.02 mg/kg SCClonidine control 2 100 DL 7E 0% 4 pellets (3 mm × 0.7 mm) 3 100 DL 7E5% Clonidine HCl; 4 pellets (3 mm × 0.7 mm) 4 100 DL 5E 5% 3 pellets (3mm × 0.7 mm) 5 100 DL 5E 7% 3 pellets (3 mm × 0.7 mm) 6 100 DL 7E 7% 3pellets (3 mm × 0.7 mm) 7 POE 0% 5 pellets (1.5 mm × 0.7 mm) 8 POE 10and 20% clonidine-base: 5 pellets (1 20% @ 0.7 mm^(2:) 4 10% @ 1.5 mm ×0.7 mm)

The inventors have conducted the present study for a period of 64 daysand have employed the following two tests: (1) the Hargreaves test; and(2) the von Frey test. The Hargreaves Tests of Thermal Hyperalgesia wereconducted on days 7, 14, 21, 28, 35, 42, 49, 56 and 63. The von Freymonofilament test of mechanical allodynia (performed the day followingThermal testing) were conducted on days-8, 15, 22, 29, 36, 43, 50, 57and 64. The results of these tests are summarized in FIGS. 3 and 4 andshow the efficacy of clonidine of the recited time periods. Theseresults are summarized in FIGS. 3 and 4.

The pain behavioral response (measured as a percentage of baseline) forthermal hyperalgesia (FIG. 3) indicates that clonidine deliveredsubcutaneously at 0.02 mg/kg/day consistently reduced the behavioralresponse when compared to either unloaded polymer depots (100 DL 7EControl or POE Control) (58% vs. 45%). All five clonidine-loaded polymerdepots were able to reduce pain behavioral responses when compared tounloaded depot; although, each formulation experienced a drop inefficacy at some point after the initial burst of drug at implantation.The pain behavioral response (measured as a percentage of baseline) formechanical allodynia indicates that clonidine delivered subcutaneouslyat 0.02 mg/kg/day reduced the behavioral response when compared toeither unloaded polymer depots (100 DL 7E Control or POE Control).

Example 3 Clonidine Drug Depot Release Profiles

FIG. 5 is a graphic representation of an in vitro release of clonidinefrom three pellet doses as measured by percentage release and microgramsreleased (Table 2). Some formulations released 80% of the clonidine for45 days. The two, three, or four pellet doses mimics the doses thatwould be implanted in a human. All the formulations had an initial bursteffect within the first two days, where the drug depot had a 10% to 80%cumulative release. In general, formulations with the higher drug loadshad a faster release profile.

FIG. 6 is a graphic representation of the calculated daily release ofclonidine from three pellet doses as measured by micrograms released(Table 3). Some formulations released the clonidine over 60 days. Thetarget daily dose was 2.4 mg/day. All the formulations had an initialburst effect within the first two days, where the drug depot released abolus dose of about 35 to 65 mcg. In general, formulations with thehigher drug loads had a faster release profile.

FIG. 7 is a graphic representation of clonidine HCl animal studyformulations as measured by the cumulative clonidine released percentage(Table 3). Some formulations released at least 60% of the clonidine for60 days. In general, formulations with the higher drug loads had alonger release profile over 45 to 60 days.

FIG. 8 is a graphic representation of clonidine HCl release for variousformulations (Table 3) as measured by the cumulative clonidine releasedpercentage. Some formulations released at least 70% of the clonidine for60 days. In general, formulations with the higher drug loads had alonger release profile over 60 days.

FIG. 9 is a graphic representation of the cumulative in vitro releaseprofile for certain clonidine formulations (Table 3). Some formulationsreleased at least 60% of the clonidine for 60 days.

FIG. 10 is a graphic representation of the cumulative release profilesfor certain irradiated clonidine HCl formulations (Table 3). Someformulations released at least 50% of the clonidine for over 80 days.

FIG. 11 is a graphic representation of certain calculated daily releasemeasurements of clonidine from 2/3/4 pellets doses (these approximatehuman doses). Some formulations (Table 3) released clonidine for 85days.

FIG. 12 is a graphic representation of the calculated daily release ofclonidine from certain three pellet doses (Table 3). Some formulationsreleased clonidine for over 65 days.

FIG. 13 is a graphic representation of the calculated daily release ofclonidine from certain 2/3 pellet dose coaxial formulations (Table 3).Some formulations released clonidine for over 85 days.

FIG. 14 is a graphic representation of the cumulative in vitro releaseprofile for certain irradiated clonidine formulations (Table 3). Someformulations released about 50% of the clonidine for over 85 days.

FIG. 15 is a graphic representation of the calculated daily release ofclonidine for certain three pellet dose formulations (Table 3). Someformulations released clonidine for over 85 days.

FIG. 16 is a graphic representation of the micrograms of clonidinereleased for certain three pellet dose formulations (Table 3). Someformulations had an initial burst effect for about 2 days, then acontinuous daily release for over 60 days.

FIG. 17 is a graphic representation of the cumulative release percentageof clonidine for certain formulations produced as indicated in Table 1.The formulation containing 10 wt % clonidine drug load and the polymer8515 DLG 7E had about 90 cumulative release % of drug released from thedepot as long as 120 days, which is suitable for many chronic conditionsof pain and/or inflammation.

FIG. 18 is a graphic representation of the cumulative release percentageof clonidine for certain formulations produced as indicated in Table 1.The formulation containing 20 wt % clonidine drug load and the polymer8515 DLG 7E had about 90 cumulative release % of drug released from thedepot as long as 140 days, which is suitable for many chronic conditionsof pain and/or inflammation.

FIG. 19 is a graphic representation of the cumulative release percentageof clonidine for certain formulations (Table 1). Some formulationsreleased about 95% of the clonidine over 110 days.

FIG. 20 is a graphic representation of the cumulative release percentageof clonidine for one formulation (Table 1) over 60 days. The release wasrelatively continuous.

FIG. 21 is a graphic representation of the cumulative release percentageof clonidine for certain formulations (Table 1) over about 40 days.

FIG. 22 is a graphic representation of the cumulative release percentageof clonidine for certain formulations (Table 1) over about 20 days.

FIG. 23 is a graphic representation of the cumulative release percentageof clonidine (Table 1) for certain formulations over 3-5 days.

FIG. 24 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 1.All formulations had about 90 cumulative release % of drug released fromthe depot for 7 days. The formulations here had smaller size (0.75mm×0.75 mm), which increases surface area for release as compared todepots with larger diameters.

FIG. 25 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 1.All formulations had over 100 cumulative release % of drug released fromthe depot for over 30 days.

FIG. 26 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 1.Span 85 is a plasticizer for one formulation. All formulations had about30 to 50 cumulative release % of drug released from the depot for over50 days.

FIG. 27 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 1. Theformulation containing 5 wt % clonidine drug load and the polymer 8515PLGA had about 100 cumulative release % of drug released from the depotas long as over 75 days, which is suitable for many chronic conditionsof pain and/or inflammation.

FIG. 28 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 1. Theformulation containing 5 wt % clonidine drug load and the polymer 8515PLGA and Span 65 as a plasticizer had about 65 cumulative release % ofdrug released from the depot as long as 70 days, which is suitable formany chronic conditions of pain and/or inflammation.

FIG. 29 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 1.All formulations had about 90 to 110 cumulative release % of drugreleased from the depot for over 100 days, except one, which had about90 cumulative release % of drug released from the depot for about 20days.

FIG. 30 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 1.All formulations had about 55 to 85 cumulative release % of drugreleased from the depot for over 28 days.

FIG. 31 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 1. Theformulation containing 10 wt % clonidine drug load and the polymerDL-PLA had about 45 cumulative release % of drug released from the depotfor about 18 days, which may be suitable for acute conditions of painand/or inflammation.

FIG. 32 is a graphic representation of the cumulative elution percentageof clonidine for certain formulations produced as indicated in Table 2.All formulations had POE and 10% or 20% clonidine drug load. Allformulations had about 80 to 90 cumulative release % of drug releasedfrom the depot for over 120 days, except one formulation, which releaseddrug within about 35 days.

FIG. 33 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 2. Theformulation containing 10 wt % clonidine drug load and the polymer POEhad about 60% cumulative release % of drug released from the depot forabout 60 days, which may be suitable for chronic conditions of painand/or inflammation.

FIG. 34 is a graphic representation of the cumulative release percentageof clonidine for one formulation produced as indicated in Table 2. Theformulation had about 35% cumulative release % of clonidine releasedfrom the depot for about 23 days.

FIGS. 5-34 show different drug depot formulations useful for reducing,preventing or treating pain and/or inflammation from a degenerative discdisease and/or pain and inflammation of one or more facet joints.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

What is claimed is:
 1. An implantable drug depot useful for reducing, preventing or treating pain and/or inflammation from a degenerative disc and/or facet joint in a patient in need of such treatment, the implantable drug depot comprising a therapeutically effective amount of an alpha adrenergic agonist, the drug depot being implantable at or near the degenerative disc and/or facet joint to reduce, prevent or treat pain and/or inflammation from the degenerative disc and/or facet joint, wherein the drug depot is capable of releasing an effective amount of the alpha adrenergic agonist over a period of at least one day and the drug depot is in the form of an adherent gel having a modulus of elasticity in the range of about 1×10² to about 3×10⁵ dynes/cm², and the adherent gel has a pre-dosed viscosity in the range of about 1 to about 200 centipoise, and the drug depot further comprises a viscosity enhancing agent.
 2. An implantable drug depot according to claim 1, wherein the drug depot releases the alpha adrenergic agonist over a period of 3 days to 12 months and the degenerative disc comprises a disc herniation.
 3. An implantable drug depot according to claim 1, wherein the alpha adrenergic agonist comprises an alpha-2 adrenergic agonist.
 4. An implantable drug depot according to claim 3, wherein the alpha-2 adrenergic agonist comprises L-norepinephrine, clonidine, dexmetdetomidine, apraclonidine, tizanidine, brimonidine, xylometazoline, tetrahydrozoline, oxymetazoline, guanfacine, guanabenz, xylazine, moxonidine, medetomidine, rilmenidine, B-HT 933, B-HT 920, mivazerol, octopamine, or a combination thereof.
 5. An implantable drug depot according to claim 1, wherein the drug depot comprises at least one biodegradable polymer comprising one or more of poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PGA), D-lactide, D,L-lactide, L-lactide, D,L-lactide-co-ε-caprolactone, D,L-lactide-co-glycolide-co-ε-caprolactone or a combination thereof.
 6. An implantable drug depot according to claim 1, wherein the drug depot comprises a polymer and the polymer comprises about 60% to 99% of the total weight % of the drug depot.
 7. An implantable drug depot according to claim 1, wherein the drug depot releases (i) a bolus dose of the alpha adrenergic agonist at or near the degenerative disc over a period of up to 3 days and (ii) an effective amount of the alpha adrenergic agonist over a period of up to 12 months.
 8. An implantable drug depot according to claim 1, wherein the drug depot releases about 20% to about 99% of the alpha adrenergic agonist relative to a total amount of the alpha adrenergic agonist loaded in the drug depot over a period of 3 days to 12 months after the drug depot is administered at or near the degenerative disc and/or facet joint.
 9. An implantable drug depot according to claim 3, wherein the drug depot releases 0.1 mg to 100 mg of the alpha-2 adrenergic agonist over 24 to 48 hours for a period of at least 3 days to reduce, treat or prevent pain and inflammation from a degenerative disc and/or facet joint.
 10. An implantable drug depot according to claim 4, wherein the drug depot comprises from about 5 wt. % to about 15 wt. % of clonidine and at least 80 wt. % of a biodegradable polymer based on the total weight of the drug depot and the drug depot is adapted to release an effective amount of the clonidine over a period of at least 150 days.
 11. An implantable drug depot according to claim 4, wherein the drug depot is implanted within 5 cm of a disc herniation and the clonidine reduces pain and/or inflammation from the disc herniation.
 12. An implantable drug depot of claim 1, wherein the drug depot comprises particles having a particle size of 5 to 30 micrometers.
 13. An implantable drug depot useful for reducing, preventing or treating pain and/or inflammation from a degenerative disc and/or facet joint in a patient in need of such treatment, the implantable drug depot comprising a therapeutically effective amount of an alpha adrenergic agonist, the drug depot being implantable at or near the degenerative disc and/or facet joint to reduce, prevent or treat pain and/or inflammation from the degenerative disc and/or facet joint, wherein the drug depot is capable of releasing an effective amount of the alpha adrenergic agonist over a period of at least one day, wherein the drug depot comprises particles and at least 75% of the particles have a size of from about 10 micrometers to about 200 micrometers wherein the drug depot is in the form of an adherent having a modulus of elasticity in the range of about 1×10² to about 3×10⁵ dynes/cm², and the adherent gel has a pre-dosed viscosity in the range of about 1 to about 200 centipoise, and the drug depot further comprises a viscosity enhancing agent.
 14. An implantable drug depot according to claim 13, wherein the drug depot comprises particles and at least 85% of the particles have a size of from about 10 micrometers to about 200 micrometers.
 15. An implantable drug depot according to claim 14, wherein at least 95% of the particles have a size of from about 10 micrometers to about 200 micrometers.
 16. An implantable drug depot according to claim 14, wherein all of the particles have a size of from about 10 micrometers to about 200 micrometers.
 17. An implantable drug depot according to claim 13, wherein the drug depot comprises particles and at least 75% of the particles have a size of from about 20 micrometers to about 180 micrometers.
 18. An implantable drug depot according to claim 17, wherein at least 85% of the particles have a size of from about 20 micrometers to about 180 micrometers.
 19. An implantable drug depot according to claim 18, wherein at least 95% of the particles have a size of from about 20 micrometers to about 180 micrometers.
 20. An implantable drug depot according to claim 19, wherein all of the particles have a size of from about 20 micrometers to about 180 micrometers.
 21. An implantable drug depot according to claim 1, wherein the viscosity enhancing agent comprises poly-(methoxyethylmethacrylate). 